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• W2018476626 abstract "Listeria monocytogenes infection generates T helper 1 (Th1) effector memory cells and CC chemokine receptor 7 (CCR7)+ cells resembling central memory cells. We tracked endogenous L. monocytogenes-specific CD4+ T cells to determine how these memory cells are formed. Two effector cell populations were already present several days after infection. One highly expressed the T-bet transcription factor and produced Th1 memory cells in an interleukin-2 (IL-2) receptor-dependent fashion. The other resided in the T cell areas, expressed CCR7 and CXC chemokine receptor 5 (CXCR5), and like follicular helper cells depended on the Bcl6 transcription factor and inducible costimulator ligand on B cells. The CCR7+CXCR5+ effector cells produced similar memory cells that generated diverse effector cell populations in a secondary response. Thus, Th1 effector memory and follicular helper-like central memory cells are produced from early effector cell populations that diverge in response to signals from the IL-2 receptor, Bcl6, and B cells. Listeria monocytogenes infection generates T helper 1 (Th1) effector memory cells and CC chemokine receptor 7 (CCR7)+ cells resembling central memory cells. We tracked endogenous L. monocytogenes-specific CD4+ T cells to determine how these memory cells are formed. Two effector cell populations were already present several days after infection. One highly expressed the T-bet transcription factor and produced Th1 memory cells in an interleukin-2 (IL-2) receptor-dependent fashion. The other resided in the T cell areas, expressed CCR7 and CXC chemokine receptor 5 (CXCR5), and like follicular helper cells depended on the Bcl6 transcription factor and inducible costimulator ligand on B cells. The CCR7+CXCR5+ effector cells produced similar memory cells that generated diverse effector cell populations in a secondary response. Thus, Th1 effector memory and follicular helper-like central memory cells are produced from early effector cell populations that diverge in response to signals from the IL-2 receptor, Bcl6, and B cells. Bacterial infection induces central and effector CD4+ memory T cells Central memory cells resemble but are distinct from follicular helper cells Effector memory cell formation is IL-2 dependent and Bcl6 independent Central memory cell formation is Bcl6 and B cell ICOSL dependent Bacterial infection generally results in immunity (Ahmed and Gray, 1996Ahmed R. Gray D. Immunological memory and protective immunity: understanding their relation.Science. 1996; 272: 54-60Crossref PubMed Scopus (1441) Google Scholar), which is mediated by bacterial antigen-specific lymphocytes that proliferate and differentiate into long-lived memory cells. In the case of CD4+ T cells, this process involves initial proliferation of naive cells with T cell antigen receptors (TCR) specific for microbe-derived peptides bound to host major histocompatibility complex II molecules (pMHCII) (Jenkins et al., 2001Jenkins M.K. Khoruts A. Ingulli E. Mueller D.L. McSorley S.J. Reinhardt R.L. Itano A. Pape K.A. In vivo activation of antigen-specific CD4 T cells.Annu. Rev. Immunol. 2001; 19: 23-45Crossref PubMed Scopus (387) Google Scholar). The progeny of the naive cells then differentiate into specialized effector cells such as interferon-γ (IFN-γ)-producing T helper 1 (Th1) cells under the influence of cytokines such as interleukin-12 (IL-12) produced by innate immune cells. Some effector cells then survive after the infection is cleared to become long-lived quiescent memory cells (Ahmed and Gray, 1996Ahmed R. Gray D. Immunological memory and protective immunity: understanding their relation.Science. 1996; 272: 54-60Crossref PubMed Scopus (1441) Google Scholar). Memory T cells exist in at least two subsets referred to as central memory (Tcm) and effector memory (Tem) T cells (Sallusto et al., 2004Sallusto F. Geginat J. Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance.Annu. Rev. Immunol. 2004; 22: 745-763Crossref PubMed Scopus (2246) Google Scholar). Tem cells express receptors needed for migration into nonlymphoid organs and, when stimulated with the relevant pMHCII ligand, immediately produce microbicidal lymphokines (Reinhardt et al., 2001Reinhardt R.L. Khoruts A. Merica R. Zell T. Jenkins M.K. Visualizing the generation of memory CD4 T cells in the whole body.Nature. 2001; 410: 101-105Crossref PubMed Scopus (842) Google Scholar). Tcm cells express CC chemokine receptor 7 (CCR7) and L-selectin, which direct recirculation through lymph nodes. When stimulated with the relevant pMHCII ligand, Tcm cells do not produce microbicidal lymphokines immediately but proliferate to produce new effector cells, which then acquire this function (Sallusto et al., 2004Sallusto F. Geginat J. Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance.Annu. Rev. Immunol. 2004; 22: 745-763Crossref PubMed Scopus (2246) Google Scholar). Th1 effector memory (Th1em) cells arise from earlier Th1 effector cells (Harrington et al., 2008Harrington L.E. Janowski K.M. Oliver J.R. Zajac A.J. Weaver C.T. Memory CD4 T cells emerge from effector T-cell progenitors.Nature. 2008; 452: 356-360Crossref PubMed Scopus (190) Google Scholar, Löhning et al., 2008Löhning M. Hegazy A.N. Pinschewer D.D. Busse D. Lang K.S. Höfer T. Radbruch A. Zinkernagel R.M. Hengartner H. Long-lived virus-reactive memory T cells generated from purified cytokine-secreting T helper type 1 and type 2 effectors.J. Exp. Med. 2008; 205: 53-61Crossref PubMed Scopus (110) Google Scholar, Surh and Sprent, 2008Surh C.D. Sprent J. Homeostasis of naive and memory T cells.Immunity. 2008; 29: 848-862Abstract Full Text Full Text PDF PubMed Scopus (868) Google Scholar). Tem cell formation is favored by strong TCR signaling (Catron et al., 2006Catron D.M. Rusch L.K. Hataye J. Itano A.A. Jenkins M.K. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells.J. Exp. Med. 2006; 203: 1045-1054Crossref PubMed Scopus (129) Google Scholar, Sarkar et al., 2007Sarkar S. Teichgräber V. Kalia V. Polley A. Masopust D. Harrington L.E. Ahmed R. Wherry E.J. Strength of stimulus and clonal competition impact the rate of memory CD8 T cell differentiation.J. Immunol. 2007; 179: 6704-6714PubMed Google Scholar), perhaps because of a shift to glycolytic metabolism (Araki et al., 2009Araki K. Turner A.P. Shaffer V.O. Gangappa S. Keller S.A. Bachmann M.F. Larsen C.P. Ahmed R. mTOR regulates memory CD8 T-cell differentiation.Nature. 2009; 460: 108-112Crossref PubMed Scopus (1148) Google Scholar, Pearce et al., 2009Pearce E.L. Walsh M.C. Cejas P.J. Harms G.M. Shen H. Wang L.S. Jones R.G. Choi Y. Enhancing CD8 T-cell memory by modulating fatty acid metabolism.Nature. 2009; 460: 103-107Crossref PubMed Scopus (1084) Google Scholar). IL-2 receptor signaling also plays a role in Th1 effector cell development (Khoruts et al., 1998Khoruts A. Mondino A. Pape K.A. Reiner S.L. Jenkins M.K. A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism.J. Exp. Med. 1998; 187: 225-236Crossref PubMed Scopus (198) Google Scholar), perhaps as a consequence of signal transducer and activator of transcription-5 (STAT5)-mediated upregulation of the IL-12 receptor β2-chain and the Th1 cell-associated T-bet (Liao et al., 2011Liao W. Lin J.X. Wang L. Li P. Leonard W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages.Nat. Immunol. 2011; 12: 551-559Crossref PubMed Scopus (324) Google Scholar) and Blimp-1 transcription factors (Gong and Malek, 2007Gong D. Malek T.R. Cytokine-dependent Blimp-1 expression in activated T cells inhibits IL-2 production.J. Immunol. 2007; 178: 242-252PubMed Google Scholar, Pipkin et al., 2010Pipkin M.E. Sacks J.A. Cruz-Guilloty F. Lichtenheld M.G. Bevan M.J. Rao A. Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells.Immunity. 2010; 32: 79-90Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar), which repress the Bcl6 transcription factor (Shaffer et al., 2002Shaffer A.L. Lin K.I. Kuo T.C. Yu X. Hurt E.M. Rosenwald A. Giltnane J.M. Yang L. Zhao H. Calame K. Staudt L.M. Blimp-1 orchestrates plasma cell differentiation by extinguishing the mature B cell gene expression program.Immunity. 2002; 17: 51-62Abstract Full Text Full Text PDF PubMed Scopus (784) Google Scholar). Much less is known about the formation of Tcm cells. These cells may be the progeny of effector cells that receive weaker TCR signals from antigen-presenting cells that display low numbers of pMHCII ligands (Catron et al., 2006Catron D.M. Rusch L.K. Hataye J. Itano A.A. Jenkins M.K. CD4+ T cells that enter the draining lymph nodes after antigen injection participate in the primary response and become central-memory cells.J. Exp. Med. 2006; 203: 1045-1054Crossref PubMed Scopus (129) Google Scholar, van Faassen et al., 2005van Faassen H. Saldanha M. Gilbertson D. Dudani R. Krishnan L. Sad S. Reducing the stimulation of CD8+ T cells during infection with intracellular bacteria promotes differentiation primarily into a central (CD62LhighCD44high) subset.J. Immunol. 2005; 174: 5341-5350PubMed Google Scholar). Recent work indicates that Tcm cells defined by expression of CCR7 also express the B cell follicle homing receptor CXC chemokine receptor 5 (CXCR5) (Chevalier et al., 2011Chevalier N. Jarrossay D. Ho E. Avery D.T. Ma C.S. Yu D. Sallusto F. Tangye S.G. Mackay C.R. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses.J. Immunol. 2011; 186: 5556-5568Crossref PubMed Scopus (261) Google Scholar) and are potent helper cells for B cells (Chevalier et al., 2011Chevalier N. Jarrossay D. Ho E. Avery D.T. Ma C.S. Yu D. Sallusto F. Tangye S.G. Mackay C.R. CXCR5 expressing human central memory CD4 T cells and their relevance for humoral immune responses.J. Immunol. 2011; 186: 5556-5568Crossref PubMed Scopus (261) Google Scholar, MacLeod et al., 2011MacLeod M.K. David A. McKee A.S. Crawford F. Kappler J.W. Marrack P. Memory CD4 T cells that express CXCR5 provide accelerated help to B cells.J. Immunol. 2011; 186: 2889-2896Crossref PubMed Scopus (101) Google Scholar). Although expression of CXCR5 suggests that Tcm cells are related to follicular helper (Tfh) cells (Morita et al., 2011Morita R. Schmitt N. Bentebibel S.E. Ranganathan R. Bourdery L. Zurawski G. Foucat E. Dullaers M. Oh S. Sabzghabaei N. et al.Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion.Immunity. 2011; 34: 108-121Abstract Full Text Full Text PDF PubMed Scopus (895) Google Scholar), which depend on Bcl6 and provide helper signals to germinal center B cells (Crotty, 2011Crotty S. Follicular helper CD4 T cells (TFH).Annu. Rev. Immunol. 2011; 29: 621-663Crossref PubMed Scopus (2026) Google Scholar), this relationship has not been demonstrated in vivo. Here, we addressed this issue by tracing the derivation of pMHCII-specific Tcm and Tem cells induced during acute systemic infection with Listeria monocytogenes (Lm). We used a pMHCII tetramer-based approach to identify CD4+ T cells specific for two pMHCII ligands produced in C57BL/6 (B6) mice during infection with a vaccine strain of Lm bacteria. This strain, called Lm-2W, contains a mutation in the actA gene (Portnoy et al., 2002Portnoy D.A. Auerbuch V. Glomski I.J. The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity.J. Cell Biol. 2002; 158: 409-414Crossref PubMed Scopus (335) Google Scholar) and was engineered to secrete a fusion protein containing the immunogenic 2W peptide (Rees et al., 1999Rees W. Bender J. Teague T.K. Kedl R.M. Crawford F. Marrack P. Kappler J. An inverse relationship between T cell receptor affinity and antigen dose during CD4(+) T cell responses in vivo and in vitro.Proc. Natl. Acad. Sci. USA. 1999; 96: 9781-9786Crossref PubMed Scopus (232) Google Scholar) under the control of the hly promoter (Ertelt et al., 2009Ertelt J.M. Rowe J.H. Johanns T.M. Lai J.C. McLachlan J.B. Way S.S. Selective priming and expansion of antigen-specific Foxp3- CD4+ T cells during Listeria monocytogenes infection.J. Immunol. 2009; 182: 3032-3038Crossref PubMed Scopus (57) Google Scholar). After infection, these bacteria are taken into phagosomes and then completely eliminated by innate and adaptive immune mechanisms (Portnoy et al., 2002Portnoy D.A. Auerbuch V. Glomski I.J. The cell biology of Listeria monocytogenes infection: the intersection of bacterial pathogenesis and cell-mediated immunity.J. Cell Biol. 2002; 158: 409-414Crossref PubMed Scopus (335) Google Scholar). During this process, the 2W peptide and peptide 190-201 from listeriolysin O (LLOp) are produced by antigen processing and bind to I-Ab MHCII molecules on antigen-presenting cells. We detected CD4+ T cells expressing TCRs specific for these ligands by staining spleen and lymph node cells from individual mice with fluorochrome-labeled LLOp:I-Ab or 2W:I-Ab tetramers and anti-fluorochrome magnetic beads and by enriching the tetramer-bound cells on a magnetized column (Moon et al., 2007Moon J.J. Chu H.H. Pepper M. McSorley S.J. Jameson S.C. Kedl R.M. Jenkins M.K. Naive CD4(+) T cell frequency varies for different epitopes and predicts repertoire diversity and response magnitude.Immunity. 2007; 27: 203-213Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar). The cells that bound to the column were stained with antibodies specific for CD3 and a mixture of non-T cell lineage-specific markers to aid in identification of genuine CD3+ T cells (Figure 1A ). We first established the kinetics of the expansion, contraction, and memory phases of the LLOp:I-Ab-specific CD4+ T cell response. B6 mice that were not infected contained a small population of LLOp:I-Ab tetramer-binding CD3+CD4+ cells in the spleen and lymph nodes, most which were CD44lo as expected for naive cells (Figure 1B). LLOp:I-Ab tetramer-binding cells were not detected among the MHCI-restricted CD8+ T cells in the bound fraction (Figure 1B), indicating that the CD4+ cells that bound the tetramer did so via the TCR. Naive mice contained about 80 LLOp:I-Ab-specific CD4+ T cells, which upregulated CD44 after intravenous injection of 107 Lm-2W bacteria, and increased in number in the spleen and lymph nodes beginning on day 3 to a peak of ∼100,000 cells by day 7 postinfection (Figures 1C and 1D). The population then contracted by day 20 to about 10,000 CD44hi memory cells, which then slowly declined over the next year (Figure 1D). Thus, LLOp:I-Ab-specific CD4+ T cells undergo the expansion, contraction, and slow memory decline phases exhibited by other pMHCII-specific CD4+ T cell populations (Homann et al., 2001Homann D. Teyton L. Oldstone M.B. Differential regulation of antiviral T-cell immunity results in stable CD8+ but declining CD4+ T-cell memory.Nat. Med. 2001; 7: 913-919Crossref PubMed Scopus (488) Google Scholar, Pepper et al., 2010Pepper M. Linehan J.L. Pagán A.J. Zell T. Dileepan T. Cleary P.P. Jenkins M.K. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells.Nat. Immunol. 2010; 11: 83-89Crossref PubMed Scopus (227) Google Scholar). We next determined whether the LLOp:I-Ab-specific memory cell population was heterogeneous. Naive LLOp:I-Ab-specific cells expressed CCR7 but not T-bet or CXCR5 (Figure 2A ). In contrast, the LLOp:I-Ab-specific memory cell population in mice infected 60 days earlier with Lm-2W bacteria consisted of T-bethiCCR7− and T-betloCCR7+ subsets observed in a previous study of the 2W:I-Ab-specific memory cell population (Pepper et al., 2010Pepper M. Linehan J.L. Pagán A.J. Zell T. Dileepan T. Cleary P.P. Jenkins M.K. Different routes of bacterial infection induce long-lived TH1 memory cells and short-lived TH17 cells.Nat. Immunol. 2010; 11: 83-89Crossref PubMed Scopus (227) Google Scholar). In addition, we found that the CCR7+ cells, but not the CCR7− cells, expressed CXCR5 (Figure 2A). We next analyzed the peak of the primary response to determine whether effector cells with the characteristics of the later memory cells were present. PD-1 was also tested to detect Tfh cells, which express this marker and the largest amounts of CXCR5 (Crotty, 2011Crotty S. Follicular helper CD4 T cells (TFH).Annu. Rev. Immunol. 2011; 29: 621-663Crossref PubMed Scopus (2026) Google Scholar). As shown in Figure 2B, the LLOp:I-Ab-specific effector cells present on day 8 after infection were split about equally into CXCR5− and CXCR5+ populations. The CXCR5− cells were Th1 effector cells based on expression of large amounts of T-bet and lack of CCR7 (Figures 2B–2D). About 10% of the CXCR5+ cells were Tfh cells based on expression of PD-1, the largest amounts of CXCR5, and the Tfh cell lineage-defining transcription factor Bcl6 (Figures 2B and 2E). The Tfh cells expressed more T-bet than naive cells but less than the Th1 cells (Figures 2B and 2C). The CXCR5+ cells that lacked PD-1 also expressed this intermediate amount of T-bet as well as low amounts of Bcl6 (Figures 2B, 2C, and 2E). These cells expressed the most CCR7 of any of the effector cell populations (Figures 2B and 2D). Thus, the LLOp:I-Ab-specific effector cell population present on day 8 after infection consisted of T-bethiCCR7− and T-betloCCR7+ subsets with the characteristics of the two later memory cell populations, along with an additional Tfh cell subset. The T-bethiCCR7− cells present at the peak of the primary response will be referred to as Th1 effector cells and the T-betloCCR7+CXCR5+PD-1− cells as Tcm precursor cells based on their expression of CCR7. This analysis was repeated 60 days after infection to determine whether any of the effector populations entered the memory pool. At this time, about half of the memory cells resembled the Th1 effector cell population (Figures 2B–2E) and will therefore be referred to as Th1em cells. The other memory cells closely resembled the CXCR5+T-betloCCR7+ Tcm precursor cells present on day 8, with the exception of reduced expression of Bcl6 (Figures 2B–2E). The CXCR5+PD-1+ Tfh cell population that was present at the peak of the response was not detected 60 days after infection (Figure 2B). A more detailed time course experiment showed that T-bethiCXCR5− Th1 and CXCR5+PD-1−CCR7+ Tcm precursor cells peaked at day 7 and contracted to lower numbers by days 12–25 that were maintained until day 60 (Figure 2F). In contrast, the CXCR5+PD-1+Bcl6hi Tfh cell population peaked at day 7 but declined progressively until disappearing by day 60 (Figure 2F). These results suggested that some Th1 effector cells survived the contraction phase to become Th1em cells, while some Tcm precursor cells became Tcm cells. Tfh cells did not appear to enter the memory cell pool. We produced a transgenic mouse (called the r7UP mouse) to formally test the possibility that some Tcm precursor cells become Tcm cells. These mice contain a bacterial artificial chromosome with a Cre-recombinase-estrogen receptor 2-fusion protein sequence (Cre-ERT2) inserted between exon 3 and the 3′ untranslated region of the Ccr7 gene (see Figure S1A available online). These mice also contain an enhanced yellow fluorescent protein (eYFP) (Tsien, 1998Tsien R.Y. The green fluorescent protein.Annu. Rev. Biochem. 1998; 67: 509-544Crossref PubMed Scopus (4930) Google Scholar) transgene with a floxed stop cassette controlled by the constitutive ROSA 26 promoter (Figure S1A; Srinivas et al., 2001Srinivas S. Watanabe T. Lin C.S. William C.M. Tanabe Y. Jessell T.M. Costantini F. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.BMC Dev. Biol. 2001; 1: 4Crossref PubMed Scopus (2305) Google Scholar). Administration of tamoxifen allows the Cre-ERT2 protein, which is normally sequestered in the cytosol, to enter the nucleus, leading to excision of the stop cassette (Srinivas et al., 2001Srinivas S. Watanabe T. Lin C.S. William C.M. Tanabe Y. Jessell T.M. Costantini F. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus.BMC Dev. Biol. 2001; 1: 4Crossref PubMed Scopus (2305) Google Scholar) and permanent expression of eYFP in cells that expressed CCR7 at the time of tamoxifen treatment. As shown in Figure S1B, about half of the CCR7+CD4+ T cells in uninfected r7UP mice treated with tamoxifen for 5 days expressed eYFP, whereas none of the CCR7−CD4+ T cells in these mice or the CD4+ T cells in tamoxifen-treated B6 mice expressed eYFP. In addition, all the eYFP+CD44hi LLOp:I-Ab-specific cells in r7UP mice 20 days after infection with Lm-2W on day 0 and treatment with tamoxifen on days 16–20 expressed CXCR5 (Figure S1C). The CCR7+eYFP−CD4+ T cells in tamoxifen-treated r7UP mice were probably cells that had not yet deleted the stop cassette upstream of the eYFP gene after 5 days of tamoxifen treatment as observed in T cells in other Cre-ERT2 transgenic mice (Rubtsov et al., 2010Rubtsov Y.P. Niec R.E. Josefowicz S. Li L. Darce J. Mathis D. Benoist C. Rudensky A.Y. Stability of the regulatory T cell lineage in vivo.Science. 2010; 329: 1667-1671Crossref PubMed Scopus (521) Google Scholar). To test the capacity of CCR7+ effector cells to become memory cells, r7UP mice were infected with Lm-2W bacteria and labeled with tamoxifen during the period of maximal effector cell generation from days 4 to 8 when CXCR5+PD-1− cells expressed the most CCR7 of any CD44hi pMHCII-specific subset (Figure 2D). We focused on the 2W:I-Ab-specific population because its larger size provided a practical advantage. About 25% of the 2W:I-Ab-specific effector cells present on day 8 were eYFP+ (Figures 2G and 2H), and virtually all of these cells expressed CCR7 (Figures 2G and 2I). 254 days after infection and 246 days after the cessation of tamoxifen treatment, about 30% of the 2W:I-Ab-specific memory cells were again eYFP+ (Figures 2G and 2H) and the vast majority retained CCR7 (Figures 2G and 2I). Therefore, some early CCR7+ effector cells produce stable CCR7+ Tcm cells. Expression of CXCR5 suggested that Tcm precursor cells might be a type of Tfh cell. If so, then Tcm precursor cells would be located in B cell follicles. To test this possibility, CD44hiCD4+CXCR5−PD-1− Th1, CXCR5intPD-1− Tcm, and CXCR5hiPD-1+ Tfh cells (Figure 3A ) were purified by flow cytometric sorting (Figure 3B) from CD45.2+ B6 mice 10 days after infection with Lm-2W organisms and injected into naive CD45.1+ recipients. These populations contained effector cells specific for Lm-2W-derived pMHCII ligands and other memory cells. One day after transfer, Th1 cells were located predominantly in the red pulp and T cell areas (identified as areas with sparse CD4+ T cells and IgD+ B cells or dense CD4+ T cells, respectively; Figure 3C) (Figure 3D), while Tfh cells were located primarily in follicles (identified as areas with dense IgD+ B cells, Figure 3C) (Figure 3D). In contrast, CXCR5+PD-1− Tcm cells were located predominantly in the T cell areas (Figure 3D), formally demonstrating that Tcm cells are not Tfh cells. We also determined whether CXCR5+ memory cells behaved like Tcm cells with respect to lymphokine production (Sallusto et al., 2004Sallusto F. Geginat J. Lanzavecchia A. Central memory and effector memory T cell subsets: function, generation, and maintenance.Annu. Rev. Immunol. 2004; 22: 745-763Crossref PubMed Scopus (2246) Google Scholar). Mice infected with Lm-2W bacteria 92 days earlier were injected intravenously with LLOp to restimulate LLOp:I-Ab-specific memory cells. As shown in Figures 4A and 4B , neither the T-bethiCXCR5− Th1 nor the T-betloCXCR5+ LLOp:I-Ab-specific memory cells were producing IL-2 or IFN-γ before peptide injection. Both memory cell types retained their preinjection patterns of T-bet and CXCR5 expression 2 hr after LLOp challenge (Figure 4A), allowing analysis of their lymphokine production. About 60% of the T-bet+CXCR5− Th1 memory cells produced IFN-γ and IL-2 and ∼20% made IL-2 but not IFN-γ 2 hr after injection of LLOp (Figures 4A and 4B). In contrast, about 10% of the T-betloCXCR5+ memory cells produced IFN-γ and IL-2 whereas ∼60% made IL-2 but not IFN-γ. Therefore, the LLOp:I-Ab-specific CXCR5+ memory cells are less potent IFN-γ producers than Th1em cells and rapidly produce IL-2 as expected for Tcm cells. Finally, we used an adoptive transfer approach to test whether CXCR5+ memory cells produced diverse effector cell progeny during the secondary response. CD44hiCD4+CXCR5+CCR7+ (containing 2W:I-Ab-specific Tcm cells) and CD44hiCD4+CXCR5−CCR7− (containing 2W:I-Ab-specific Th1em cells) cells were sorted from B6 mice 40 days after infection with Lm-2W organisms and injected into naive CD45.1+ recipients. The recipient mice were then challenged with Lm-2W organisms, and the phenotype of the donor and recipient 2W:I-Ab-specific T cells (Figure 4C) was assessed 6 days later. As shown in Figures 4C and 4D, 96% of the effector cell progeny of CCR7−CXCR5− Th1em cells were Th1 cells. In contrast, the progeny of CXCR5+ memory cells consisted of 70% Th1 cells, 21% Tcm precursor cells, and 5% Tfh cells, whereas the naive cells of the recipients produced 44% Th1 cells, 43% Tcm precursor cells, and 8% Tfh cells. Therefore, although CXCR5+ memory cells have a tendency to produce Th1 effector cells, they are more efficient than Tem cells at generating Tcm precursor cells and Tfh cells. The results were consistent with the possibility that Th1 effector and Tcm precursor cells generated early in the primary response gave rise to Th1em and Tcm cells. We examined very early times after Lm-2W infection to get insight into the origins of these populations. The IL-2 receptor alpha chain (CD25) was included in the analysis because it has been implicated in Th1 cell development in other systems (Khoruts et al., 1998Khoruts A. Mondino A. Pape K.A. Reiner S.L. Jenkins M.K. A natural immunological adjuvant enhances T cell clonal expansion through a CD28-dependent, interleukin (IL)-2-independent mechanism.J. Exp. Med. 1998; 187: 225-236Crossref PubMed Scopus (198) Google Scholar, Liao et al., 2011Liao W. Lin J.X. Wang L. Li P. Leonard W.J. Modulation of cytokine receptors by IL-2 broadly regulates differentiation into helper T cell lineages.Nat. Immunol. 2011; 12: 551-559Crossref PubMed Scopus (324) Google Scholar). Naive LLOp:I-Ab-specific cells in uninfected mice did not express CXCR5 or CD25 (Figure 5A ). Remarkably, the LLOp:I-Ab-specific population had already split equally into CXCR5− and CXCR5+ subsets only 3 days after infection (Figure 5A) when expansion of LLOp:I-Ab-specific T cells was first detected (Figure 1D). Notably, most of the CXCR5− cells also expressed CD25 and most of the CXCR5+ cells did not (Figure 5A). On day 4 after infection, the CXCR5− cells expressed more T-bet than CXCR5+ cells (Figure 5B). These findings raised the possibility that CD25 was required for the development of the CXCR5− Th1 effector cells. This premise was tested in chimeras containing a mixture of wild-type and CD25-deficient T cells so that both populations could be monitored under conditions where normal regulatory T cells were present to prevent the autoimmunity that occurs in intact CD25-deficient mice (Willerford et al., 1995Willerford D.M. Chen J. Ferry J.A. Davidson L. Ma A. Alt F.W. Interleukin-2 receptor alpha chain regulates the size and content of the peripheral lymphoid compartment.Immunity. 1995; 3: 521-530Abstract Full Text PDF PubMed Scopus (938) Google Scholar). As shown in Figures 5C and 5D, CD25-deficient LLOp:I-Ab-specific naive cells were about one tenth as good as wild-type cells at generating T-bethiCXCR5− Th1 cells in these chimeras 5 days after Lm-2W infection but were as good as wild-type cells at generating CXCR5+PD-1− Tcm precursor cells and CXCR5+PD-1+ Tfh cells. CD25 is therefore required for the optimal development of T-bethiCXCR5− Th1 cells but not the other effector cell populations. We also examined the role of Bcl6 in the development of Tcm cells. Bcl6 was expressed in higher amounts in the CXCR5+ subset of LLOp:I-Ab-specific cells 3 days after Lm-2W infection than in the CXCR5− subset (Figure 6A ). Radiation bone marrow chimeras containing a mixture of wild-type and Bcl6−/− (Dent et al., 1997Dent A.L. Shaffer A.L. Yu X. Allman D. Staudt L.M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6.Science. 1997; 276: 589-592Crossref PubMed Scopus (768) Google Scholar) cells were used to test whether Bcl6 was required for the formation of CXCR5+ T cells. Indeed, Bcl6-deficient CD4+ T cells failed to generate early LLOp:I-Ab-specific CXCR5+ cells on day 3 (Figures 6A and 6B). Similarly, CXCR5+PD-1− Tcm precursor cells and CXCR5+PD-1+ Tfh cells were generated at only 1% of the amount generated from wild-type CD4+ T cells 7 days after Lm-2W infection (Figures 6C and 6D). The Bcl6-deficient LLOp:I-Ab-specific T cells present on day 7 were all T-bethi, indicating that T-betlo Tcm cell precursors were truly absent and had not simply lost CXCR5 (Figure 6C). We also produced radiation bone marrow chimeras containing a mixture of wild-type and Bcl6+/− T cells to test the dependence of the two types of CXCR5+ effector cells on the amount of Bcl6 expressed. As shown in Figure 6D, LLOp:I-Ab-specific Bcl6+/− Tcm precursor cells formed only slightly less well than wild-type cells 7 days after Lm-2W infection, whereas Bcl6+/− Tfh cells were generated at 10% of the amount generated from wild-type T cells. These results demonstrate" @default.
• W2018476626 created "2016-06-24" @default.
• W2018476626 creator A5007540366 @default.
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• W2018476626 title "Opposing Signals from the Bcl6 Transcription Factor and the Interleukin-2 Receptor Generate T Helper 1 Central and Effector Memory Cells" @default.
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