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• W2025827372 abstract "•CD4+ T cell effector functions are elicited by MAMPs during bacterial infection•T-cell-intrinsic MyD88, IL-18R, and IL-33R maximize stimulation of CD4+ Th1 cells•TLR and inflammasome components amplify CD4+ T cell responses•Loss of innate T cell stimulation impairs host resolution of bacterial infection T cell effector functions can be elicited by noncognate stimuli, but the mechanism and contribution of this pathway to the resolution of intracellular macrophage infections have not been defined. Here, we show that CD4+ T helper 1 (Th1) cells could be rapidly stimulated by microbe-associated molecular patterns during active infection with Salmonella or Chlamydia. Further, maximal stimulation of Th1 cells by lipopolysaccharide (LPS) did not require T-cell-intrinsic expression of toll-like receptor 4 (TLR4), interleukin-1 receptor (IL-1R), or interferon-γ receptor (IFN-γR) but instead required IL-18R, IL-33R, and adaptor protein MyD88. Innate stimulation of Th1 cells also required host expression of TLR4 and inflammasome components that together increased serum concentrations of IL-18. Finally, the elimination of noncognate Th1 cell stimulation hindered the resolution of primary Salmonella infection. Thus, the in vivo bactericidal capacity of Th1 cells is regulated by the response to noncognate stimuli elicited by multiple innate immune receptors. T cell effector functions can be elicited by noncognate stimuli, but the mechanism and contribution of this pathway to the resolution of intracellular macrophage infections have not been defined. Here, we show that CD4+ T helper 1 (Th1) cells could be rapidly stimulated by microbe-associated molecular patterns during active infection with Salmonella or Chlamydia. Further, maximal stimulation of Th1 cells by lipopolysaccharide (LPS) did not require T-cell-intrinsic expression of toll-like receptor 4 (TLR4), interleukin-1 receptor (IL-1R), or interferon-γ receptor (IFN-γR) but instead required IL-18R, IL-33R, and adaptor protein MyD88. Innate stimulation of Th1 cells also required host expression of TLR4 and inflammasome components that together increased serum concentrations of IL-18. Finally, the elimination of noncognate Th1 cell stimulation hindered the resolution of primary Salmonella infection. Thus, the in vivo bactericidal capacity of Th1 cells is regulated by the response to noncognate stimuli elicited by multiple innate immune receptors. Pathogen-specific lymphocytes recirculate at low frequency between the blood and secondary lymphoid tissues and undergo rapid expansion in response to infection (Kwok et al., 2012Kwok W.W. Tan V. Gillette L. Littell C.T. Soltis M.A. LaFond R.B. Yang J. James E.A. DeLong J.H. Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire.J. Immunol. 2012; 188: 2537-2544Crossref PubMed Scopus (83) Google Scholar, 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). As clonal expansion occurs, responding T cells integrate local instructional stimuli to acquire effector functions tailored to combat different pathogen types (Obar and Lefrançois, 2010Obar J.J. Lefrançois L. Memory CD8+ T cell differentiation.Ann. N Y Acad. Sci. 2010; 1183: 251-266Crossref PubMed Scopus (107) Google Scholar, Zhu et al., 2010Zhu J. Yamane H. Paul W.E. Differentiation of effector CD4 T cell populations (∗).Annu. Rev. Immunol. 2010; 28: 445-489Crossref PubMed Scopus (2263) Google Scholar). The expansion and functional maturation of individual T cell clones are tightly regulated by pathogen-specific T cell receptors (TCRs) that recognize microbial peptides in the context of host major histocompatibility complex (MHC) molecules. Thus, the adaptive immune response to infection produces a large population of antigen-specific effector T cells with appropriate functional activities to combat invading microbes. Although the initial activation and expansion of pathogen-specific T cells are controlled by TCR ligation, the subsequent signals for inducing T cell effector functions are incompletely understood. In a noninfectious context, the elicitation of effector functions by tissue-resident CD4+ T cells requires TCR recognition of cognate antigen presented by local antigen-presenting cells (McLachlan et al., 2009McLachlan J.B. Catron D.M. Moon J.J. Jenkins M.K. Dendritic cell antigen presentation drives simultaneous cytokine production by effector and regulatory T cells in inflamed skin.Immunity. 2009; 30: 277-288Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). However, a lower threshold for stimulating activated effector T cells might be advantageous when the host confronts a replicating pathogen, especially one that can manipulate host MHC expression (Griffin and McSorley, 2011Griffin A.J. McSorley S.J. Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda.Mucosal Immunol. 2011; 4: 371-382Crossref PubMed Scopus (101) Google Scholar). Indeed, inflammatory cytokines, notably interleukin-12 (IL-12) and IL-18, cause noncognate stimulation of effector CD8+ T cells (Beadling and Slifka, 2005Beadling C. Slifka M.K. Differential regulation of virus-specific T-cell effector functions following activation by peptide or innate cytokines.Blood. 2005; 105: 1179-1186Crossref PubMed Scopus (43) Google Scholar, Berg et al., 2002Berg R.E. Cordes C.J. Forman J. Contribution of CD8+ T cells to innate immunity: IFN-gamma secretion induced by IL-12 and IL-18.Eur. J. Immunol. 2002; 32: 2807-2816Crossref PubMed Scopus (145) Google Scholar, Freeman et al., 2012Freeman B.E. Hammarlund E. Raué H.P. Slifka M.K. Regulation of innate CD8+ T-cell activation mediated by cytokines.Proc. Natl. Acad. Sci. USA. 2012; 109: 9971-9976Crossref PubMed Scopus (149) Google Scholar). During bacterial infections, the production of inflammatory cytokines can be initiated by host recognition of conserved molecular patterns via multiple innate immune receptors (Broz and Monack, 2011Broz P. Monack D.M. Molecular mechanisms of inflammasome activation during microbial infections.Immunol. Rev. 2011; 243: 174-190Crossref PubMed Scopus (194) Google Scholar). Thus, bacterial flagellin can efficiently drive noncognate stimulation of CD8+ memory T cells in a process that involves dendritic cell sensing of cytosolic flagellin by NLR family CARD-domain-containing protein 4 (NLRC4) (Kupz et al., 2012Kupz A. Guarda G. Gebhardt T. Sander L.E. Short K.R. Diavatopoulos D.A. Wijburg O.L. Cao H. Waithman J.C. Chen W. et al.NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells.Nat. Immunol. 2012; 13: 162-169Crossref PubMed Scopus (124) Google Scholar). However, the role of toll-like receptor (TLR) and inflammasome signaling in the elicitation of T cell effector functions is currently unclear. Such noncognate stimulation pathways might allow T cell effector functions to be induced rapidly in an inflammatory context and provide an evolutionary advantage for the host in combating bacterial pathogens. The efferent phase of the CD4+ Th1 cell response to an intramacrophage pathogen has the potential to be relatively nonspecific, given that it consists of macrophage activation by locally produced interferon-γ (IFN-γ). Although cytokine secretion might be restricted to the synapse during cognate (antigen receptor agonist) stimulation, CD4+ Th1 cells can activate macrophages in the absence of cognate stimuli and also provide cross-protection against unrelated coinfecting microbes (MacKaness, 1964MacKaness G.B. The Immunological Basis of Acquired Cellular Resistance.J. Exp. Med. 1964; 120: 105-120Crossref PubMed Scopus (434) Google Scholar, Müller et al., 2012Müller A.J. Filipe-Santos O. Eberl G. Aebischer T. Späth G.F. Bousso P. CD4+ T cells rely on a cytokine gradient to control intracellular pathogens beyond sites of antigen presentation.Immunity. 2012; 37: 147-157Abstract Full Text Full Text PDF PubMed Scopus (98) Google Scholar, Poo et al., 1988Poo W.J. Conrad L. Janeway Jr., C.A. Receptor-directed focusing of lymphokine release by helper T cells.Nature. 1988; 332: 378-380Crossref PubMed Scopus (229) Google Scholar). Even though Th1 cell secretion of IFN-γ can be induced by cognate antigen and MHC class II molecules presented on infected phagocytes, it can also occur in the presence of cytokines (Robinson et al., 1997Robinson D. Shibuya K. Mui A. Zonin F. Murphy E. Sana T. Hartley S.B. Menon S. Kastelein R. Bazan F. O’Garra A. IGIF does not drive Th1 development but synergizes with IL-12 for interferon-gamma production and activates IRAK and NFkappaB.Immunity. 1997; 7: 571-581Abstract Full Text Full Text PDF PubMed Scopus (638) Google Scholar, Takeda et al., 1998Takeda K. Tsutsui H. Yoshimoto T. Adachi O. Yoshida N. Kishimoto T. Okamura H. Nakanishi K. Akira S. Defective NK cell activity and Th1 response in IL-18-deficient mice.Immunity. 1998; 8: 383-390Abstract Full Text Full Text PDF PubMed Scopus (782) Google Scholar) or TLR ligation (Caramalho et al., 2003Caramalho I. Lopes-Carvalho T. Ostler D. Zelenay S. Haury M. Demengeot J. Regulatory T cells selectively express toll-like receptors and are activated by lipopolysaccharide.J. Exp. Med. 2003; 197: 403-411Crossref PubMed Scopus (850) Google Scholar, Reynolds et al., 2010Reynolds J.M. Pappu B.P. Peng J. Martinez G.J. Zhang Y. Chung Y. Ma L. Yang X.O. Nurieva R.I. Tian Q. Dong C. Toll-like receptor 2 signaling in CD4(+) T lymphocytes promotes T helper 17 responses and regulates the pathogenesis of autoimmune disease.Immunity. 2010; 32: 692-702Abstract Full Text Full Text PDF PubMed Scopus (240) Google Scholar). However, the signals that drive noncognate stimulation of CD4+ Th1 cells and the contribution of this pathway to bacterial clearance have not been clearly defined in vivo. In this study, we examined the mechanism and contribution of noncognate T cell stimulation to the resolution of intramacrophage infection. Expanded T-bet+CD4+ T cells in Salmonella- and Chlamydia-infected mice were induced to secrete IFN-γ by brief in vivo exposure to ligands for TLR2, TLR4, and TLR5, and this required T-cell-intrinsic expression of the adaptor protein MyD88 and IL-18R, as well as IL-33R, in this amplification of Th1 cell responses. Generating an inflammatory environment favoring noncognate stimulation of Th1 cells required host expression of TLR and inflammasome components, which together enhanced concentrations of circulating IL-18. CD8+ T cells were able to respond in a similar manner but made a smaller contribution to bacterial clearance. Mice lacking T-cell-intrinsic expression of MyD88 had impaired ability to control primary Salmonella infection, demonstrating the importance of noncognate responses to the resolution of an intramacrophage infection. Overall, these data show that noncognate stimulation of T cells can occur in response to innate inflammatory cues and contribute to defense against intramacrophage pathogens. Salmonella infection of C57BL/6 mice induced the expansion of splenic CD44hiCD4+ and CD8+ T cell populations that persisted as a major fraction of the T cell pool until bacterial clearance occurred, approximately 5–8 weeks later (Figure 1A) (Srinivasan et al., 2004Srinivasan A. Foley J. McSorley S.J. Massive number of antigen-specific CD4 T cells during vaccination with live attenuated Salmonella causes interclonal competition.J. Immunol. 2004; 172: 6884-6893Crossref PubMed Scopus (61) Google Scholar). The majority of CD4+ T cells responding to Salmonella infection expressed the transcription factor T-bet (Figure 1B), consistent with a requirement for Th1 cells in the resolution of intramacrophage infections (Griffin and McSorley, 2011Griffin A.J. McSorley S.J. Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda.Mucosal Immunol. 2011; 4: 371-382Crossref PubMed Scopus (101) Google Scholar). A small population of CD4+ (<5%) or CD8+ (<2%) T cells in the spleen of Salmonella-infected mice were found to be actively secreting IFN-γ; these were part of the expanded CD44hi population and were undetectable in uninfected mice (Figure 1C, “no stim”). However, intravenous injection of infected mice with ultrapure lipopolysaccharide (LPS) induced IFN-γ secretion from approximately 30%–50% of CD4+ T cells and 5%–20% of CD8+ T cells within 4 hours, whereas a response to innate receptor stimuli was not detected in uninfected recipients (Figure 1C). Among CD4+ T cells, LPS-induced IFN-γ production was confined to T-bet+ cells, and typically 50%–70% of all T-bet+CD4+ T cells participated in this innate response at the peak of infection (Figures 1D and 1E). As Salmonella infection resolved around day 35 (Srinivasan et al., 2004Srinivasan A. Foley J. McSorley S.J. Massive number of antigen-specific CD4 T cells during vaccination with live attenuated Salmonella causes interclonal competition.J. Immunol. 2004; 172: 6884-6893Crossref PubMed Scopus (61) Google Scholar), the proportion of T-bet+CD4+ T cells able to respond to innate stimuli correspondingly decreased (Figure 1E). However, a small population (5%–10%) of T-bet+CD4+ T cells retained the ability to respond rapidly to innate stimuli for at least 24 weeks after primary infection (Figure 1E). A similar response was detected among activated CD8+ T cells, but the magnitude was lower than that among CD4+ T cells at each time point (Figure 1E). There were no other major splenic cell populations that produced IFN-γ in response to innate stimuli (Figure S1, available online), indicating that CD4+ and CD8+ T cells are the major IFN-γ-producing cells in this model. To determine whether innate amplification of CD4+ Th1 cell effector function was a process unique to Salmonella infection, we examined C57BL/6 mice infected with Chlamydia muridarum, another common intramacrophage pathogen (Farris and Morrison, 2011Farris C.M. Morrison R.P. Vaccination against Chlamydia genital infection utilizing the murine C. muridarum model.Infect. Immun. 2011; 79: 986-996Crossref PubMed Scopus (92) Google Scholar). T-bet+CD4+ T cells in the spleen of C57BL/6 mice infected with Chlamydia muridarum produced IFN-γ rapidly in response to LPS stimulation (Figures 2A and 2B ). LPS injection also caused a small population of CD8+ T cells to secrete IFN-γ (Figure 2B). As in the Salmonella-infection model, little IFN-γ secretion was detectable in CD4+ T cells of uninfected mice injected with LPS or in Chlamydia-infected mice prior to LPS injection (Figures 2A and 2B). Next, we examined whether other TLR ligands had the capacity to induce IFN-γ production from T-bet+CD4+ T cells by injecting Salmonella-infected mice with LPS (recognized by TLR4), flagellin (TLR5), Pam3CSK4 (TLR1 and TLR2), CpG DNA (TLR9), or Imiquimod (TLR7). Injection of LPS, flagellin, or Pam3CSK4 amplified the production of IFN-γ from T-bet+CD4+ T cells in Salmonella-infected mice, and LPS acted as the most effective inducer (Figures 2C and 2D). A small percentage of CD8+ T cells also produced IFN-γ in response to each of these stimuli (Figure 2D). In contrast, the injection of CpG DNA or Imiquimod failed to induce IFN-γ production over baseline production detected in CD4+ and CD8+ T cells from Salmonella-infected mice (Figures 2C and 2D). LPS stimulation of T-bet+CD4+ and CD44+CD8+ T cells was greatest when 25 μg of LPS was used; however, a rapid innate response was also detectable when as little as 100 ng of LPS was injected (Figure 2E). Together, these results demonstrate that innate stimulation of CD4+ and CD8+ T cells can occur rapidly in response to a variety of microbial stimuli and that this capability is a common feature of the immune response to intramacrophage infections. Mixed bone marrow (BM) chimeric mice were generated to define the T-cell-intrinsic requirements for innate amplification of CD4+ and CD8+ T cell effector functions. Congenically marked (CD90.2+CD45.1+) mice were irradiated and reconstituted with a 1:1 mixture of BM from wild-type (WT) mice (CD90.1+CD45.2+) and a variety of gene-deficient (CD90.2+CD45.2+) mice (Figure 3A), allowing direct comparison of WT and gene-deficient T cells within a single Salmonella-infected host. As expected, CD4+ and CD8+ T cells in Salmonella-infected, nonchimeric, TLR4-deficient mice were unable to produce IFN-γ in response to innate stimulation with LPS (Figure S2). However, in Salmonella-infected chimeras containing a 1:1 mix of both deficient and WT cells, both WT and TLR4-deficient CD4+ and CD8+ T cells responded equally well to LPS stimulation (Figure 3B and Figure S3A). Next, we utilized mixed BM chimeras to examine the requirement for MyD88, an essential component of most TLR and IL-1-like receptor (IL-1R) signaling. CD4+ and CD8+ T cells lacking expression of MyD88 were unable to respond to LPS injection, whereas WT CD4+ and CD8+ T cells in the same mouse generated robust IFN-γ responses (Figure 3C and Figure S3B). Thus, both CD4+ and CD8+ T cells require expression of MyD88, but not TLR4, in order to rapidly respond to innate stimuli. Given the requirement for MyD88 expression in T cells, we generated mixed BM chimeras to examine various cytokine receptors that utilize this adaptor molecule in downstream signaling (IL-1R, IL-18R, IL-33R, and IFN-γR). Loss of IL-1R or IFN-γR expression had no effect on the innate CD4+ or CD8+ T cell responses to LPS in Salmonella-infected mice (Figures 4A and 4B and Figures S3C and S3D). In marked contrast, CD4+ or CD8+ T cell expression of IL-18R was essential for rapid amplification of IFN-γ production in response to LPS stimulation (Figure 4C and Figure S3E). Interestingly, although IL-33 is usually associated with Th2 cell responses (Lloyd, 2010Lloyd C.M. IL-33 family members and asthma - bridging innate and adaptive immune responses.Curr. Opin. Immunol. 2010; 22: 800-806Crossref PubMed Scopus (129) Google Scholar), T-bet+CD4+ T cells lacking the expression of IL-33R demonstrated consistently lower IFN-γ responses to LPS (Figure 4D). Together, these data indicate that effector CD4+ Th1 cells respond directly to IL-18 and IL-33 in order to maximize IFN-γ production in the presence of innate stimuli. Given the requirement for T cell expression of IL-18R and IL-33R, we examined cytokine production in the spleen and liver during innate stimulation with LPS. By quantitative RT-PCR (qRT-PCR) analysis, a modest increase in IFN-γ mRNA was detected in the liver and spleen of uninfected mice that had been injected with LPS (Table 1). However, LPS injection of uninfected mice had little effect on IL-12, IL-18, or IL-33 mRNA in the spleen and only modestly increased these mRNAs in the liver (Table 1). In contrast, injection of LPS into Salmonella-infected mice (day 14 postinfection) caused a notable increase in spleen and liver IFN-γ, IL-12, IL-18, and IL-33 mRNA, and the IL-33 increase was particularly prominent in the liver (Table 1). At the protein level, injection of LPS into Salmonella-infected mice caused a rapid 300-fold increase in IFN-γ and a 35-fold increase in IL-18 in serum (Figures 5A and 5B ). In contrast, IL-12 and IL-33 concentrations were below the level of detection in the sera of Salmonella-infected mice, even after injection with LPS (data not shown), suggesting that the production of these cytokines is restricted to infected tissue or subject to additional posttranscriptional controls. Injection of flagellin or Pam3CSK4 into Salmonella-infected mice also caused a marked increase in serum IFN-γ and IL-18, whereas injection of Imiquimod did not (Figures 5C and 5D), supporting the observation in Figure 1 that T cells can respond to LPS, flagellin, or Pam3CSK4 stimulation, but not Imiquimod stimulation.Table 1LPS Stimulation Leads to Increased mRNA Expression of IFN-γ, IL-12, IL-18, and IL-33C57BL/6 MiceEffect of LPS (Relative to That on Unstimulated Controls)IFN-γIL-12IL-18IL-33SpleenUninfected1111Uninfected + LPS8.670.991.301.60Salmonella-infected1111Salmonella-infected + LPS22.024.522.265.35LiverUninfected1111Uninfected + LPS11.071.471.966.16Salmonella-infected1111Salmonella-infected + LPS27.95.362.616.2C57BL/6 mice were infected i.v. with 5 × 105 Salmonella, and 2 weeks later, infected or uninfected mice were injected i.v. with LPS. Spleens and livers were harvested 4 hours later, and qRT-PCR was performed on extracted mRNA. Numbers shown are normalized to Gapdh expression and indicate the fold-change increase over unstimulated mice. See also Table S2. Open table in a new tab C57BL/6 mice were infected i.v. with 5 × 105 Salmonella, and 2 weeks later, infected or uninfected mice were injected i.v. with LPS. Spleens and livers were harvested 4 hours later, and qRT-PCR was performed on extracted mRNA. Numbers shown are normalized to Gapdh expression and indicate the fold-change increase over unstimulated mice. See also Table S2. A requirement for NLRC4 in flagellin-mediated noncognate stimulation of CD8+ T cells has previously been reported (Kupz et al., 2012Kupz A. Guarda G. Gebhardt T. Sander L.E. Short K.R. Diavatopoulos D.A. Wijburg O.L. Cao H. Waithman J.C. Chen W. et al.NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells.Nat. Immunol. 2012; 13: 162-169Crossref PubMed Scopus (124) Google Scholar), suggesting that direct recognition of injected flagellin by inflammasome components occurs. Because NLRC4 and NLRP3 play redundant roles in the recognition of Salmonella (Broz et al., 2010Broz P. Newton K. Lamkanfi M. Mariathasan S. Dixit V.M. Monack D.M. Redundant roles for inflammasome receptors NLRP3 and NLRC4 in host defense against Salmonella.J. Exp. Med. 2010; 207: 1745-1755Crossref PubMed Scopus (411) Google Scholar), we examined whether NLRC4 and NLRP3 were required for noncognate stimulation of CD4+ T cells by LPS or flagellin. Whereas the injection of WT mice with flagellin or LPS induced a rapid increase in serum IL-18, this same response was markedly lower in mice deficient in both NLRC4 and NLRP3 (Figure 5E). This reduced IL-18 production in response to flagellin or LPS correlated with a severely curtailed innate CD4+ T cell response to either stimulus in mice lacking NLRC4 and NLRP3 (Figure 5F). A similar requirement for NLRC4 and NLRP3 in the induction of IFN-γ by CD8+ T cells was also observed (Figure S4). A requirement for NLRC4 and NLRP3 in the innate response of CD4+ T cells to LPS suggested that inflammasome stimulation by live bacteria is required for maximal CD4+ T cell responses to occur. However, CD4+ and CD8+ T cells in mice infected with flagellin-deficient Salmonella responded normally to innate stimulation by ultrapure LPS (Figure 5G and Figure S4B), indicating that bacterial ligands other than flagellin can also drive the inflammasome activation required for innate T cell stimulation. Together, these data indicate that rapid production of IL-18 in vivo is a critical regulatory checkpoint for noncognate CD4+ and CD8+ T cell responses to inflammatory stimuli and that this process requires TLR recognition of bacterial ligands and NLR activation in infected mice. In Salmonella-infected mice, depletion of CD4+ T cells severely limited bacterial clearance from the spleen and liver (Figures 6A and 6B ), confirming the importance of CD4+ T cells to host protective immunity (Nauciel, 1990Nauciel C. Role of CD4+ T cells and T-independent mechanisms in acquired resistance to Salmonella typhimurium infection.J. Immunol. 1990; 145: 1265-1269PubMed Google Scholar). Depletion of CD8+ T cells also hindered bacterial clearance (Figures 6A and 6B), consistent with a secondary role for CD8+ T cells in host protection (Lee et al., 2012aLee S.J. Dunmire S. McSorley S.J. MHC class-I-restricted CD8 T cells play a protective role during primary Salmonella infection.Immunol. Lett. 2012; 148: 138-143Crossref PubMed Scopus (44) Google Scholar, Nauciel, 1990Nauciel C. Role of CD4+ T cells and T-independent mechanisms in acquired resistance to Salmonella typhimurium infection.J. Immunol. 1990; 145: 1265-1269PubMed Google Scholar). Although both CD4+ and CD8+ T cells participate in Salmonella clearance, the contribution of cognate versus noncognate stimulation is currently unknown. In order to assess the in vivo relevance of noncognate T cell activation, we examined the course of Salmonella infection in loxP-Myd88 mice expressing Cre-recombinase driven by the Lck promoter (Myd88fl/fl Lck-cre mice). Early clearance of Salmonella was unaffected in Myd88fl/fl Lck-cre mice (data not shown), consistent with the dependence of early control on the innate immune compartment (Griffin and McSorley, 2011Griffin A.J. McSorley S.J. Development of protective immunity to Salmonella, a mucosal pathogen with a systemic agenda.Mucosal Immunol. 2011; 4: 371-382Crossref PubMed Scopus (101) Google Scholar). However, beginning around 3 weeks postinfection, approximately 1 in 6 Myd88fl/fl Lck-cre mice succumbed to primary Salmonella infection (Figure 6C). Furthermore, at 5 weeks postinfection, the spleens of the remaining Myd88fl/fl Lck-cre mice displayed significantly higher bacterial loads than did WT and heterozygous littermate controls (Figures 6D and 6E). Thus, the ability of T cells to respond to MyD88-dependent signals is an important component in resolving infection with an intramacrophage pathogen. Approximately 50 years ago, George MacKaness reported that Brucella-infected mice display transient cross-reactive protection against other intramacrophage pathogens and that this effect correlates with the induction of a cellular immune response (MacKaness, 1964MacKaness G.B. The Immunological Basis of Acquired Cellular Resistance.J. Exp. Med. 1964; 120: 105-120Crossref PubMed Scopus (434) Google Scholar). The mechanistic basis of this cross-bacterial protection is usually understood to derive from the indiscriminate killing activity of activated macrophages via reactive oxygen and nitrogen species (Fang, 2004Fang F.C. Antimicrobial reactive oxygen and nitrogen species: concepts and controversies.Nat. Rev. Microbiol. 2004; 2: 820-832Crossref PubMed Scopus (1228) Google Scholar). A lack of target specificity in the efferent phase of host defense against intramacrophage pathogens is likely to have evolved to combat superinfection or coinfections and is held in check by TCR-mediated clonal expansion and effector development (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). However, it has become apparent that after clonal expansion, effector T cells can be activated by a variety of noncognate stimuli (Beadling and Slifka, 2005Beadling C. Slifka M.K. Differential regulation of virus-specific T-cell effector functions following activation by peptide or innate cytokines.Blood. 2005; 105: 1179-1186Crossref PubMed Scopus (43) Google Scholar, Berg et al., 2002Berg R.E. Cordes C.J. Forman J. Contribution of CD8+ T cells to innate immunity: IFN-gamma secretion induced by IL-12 and IL-18.Eur. J. Immunol. 2002; 32: 2807-2816Crossref PubMed Scopus (145) Google Scholar, Freeman et al., 2012Freeman B.E. Hammarlund E. Raué H.P. Slifka M.K. Regulation of innate CD8+ T-cell activation mediated by cytokines.Proc. Natl. Acad. Sci. USA. 2012; 109: 9971-9976Crossref PubMed Scopus (149) Google Scholar, Guo et al., 2012Guo L. Junttila I.S. Paul W.E. Cytokine-induced cytokine production by conventional and innate lymphoid cells.Trends Immunol. 2012; 33: 598-606Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, Kupz et al., 2012Kupz A. Guarda G. Gebhardt T. Sander L.E. Short K.R. Diavatopoulos D.A. Wijburg O.L. Cao H. Waithman J.C. Chen W. et al.NLRC4 inflammasomes in dendritic cells regulate noncognate effector function by memory CD8+ T cells.Nat. Immunol. 2012; 13: 162-169Crossref PubMed Scopus (124) Google Scholar, Soudja et al., 2012Soudja S.M. Ruiz A.L. Marie J.C. Lauvau G. Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion.Immunity. 2012; 37: 549-562Abstract Full Text Full Text PDF PubMed Scopus (187) Google Scholar), suggesting that cognate stimulation might not be required in infected tissues. However, the role of noncognate T cell stimulation in defense against intramacrophage pathogens is poorly understood. Several prior studies have documented the expansion of a large population of activated CD4+ T cells in mice infected with Salmonella (Mittrücker et al., 2002Mittrücker H.W. Köhler A. Kaufmann S.H. Characterization of the murine T-lymphocyte response to Salmonella enterica serovar Typhimurium infection.Infect. Immun. 2002; 70: 199-203Crossref PubMed Scopus (95) Google Scholar, Srinivasan et al., 2004Srinivasan A. Foley J. McSorley S.J. Massive number of antigen-specific CD4 T cells during vaccination with live attenuated Salmonella causes interclonal competition.J. Immunol. 2004; 172: 6884-6893Crossref PubMed Scopus (61) Google Scholar, Srinivasan et al., 2007Srinivasan A. Salazar-Gonzalez R.M. Jarcho M. Sandau M.M. Lefrancois L. McSorley S.J. Innate immune activation of CD4 T cells in salmonella-infected mice is dependent on IL-18.J. Immunol. 2007; 178: 6342-6349Crossref PubMed Scopus (53) Google Scholar). Although antigen-specific T cells can be visualized in this infection model with the use of tetramers (Lee et al., 2012bLee S.J. McLachlan J.B. Kurtz J.R. Fan" @default.
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• W2025827372 date "2014-02-01" @default.
• W2025827372 modified "2023-10-15" @default.
• W2025827372 title "Toll-like Receptor and Inflammasome Signals Converge to Amplify the Innate Bactericidal Capacity of T Helper 1 Cells" @default.
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