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• W2272264107 abstract "T follicular helper (Tfh) cells provide crucial support to antigen-specific B cells. In this issue of Immunity, Schultz et al., 2016Schultz B.T. Teigler J.E. Pissani F. Oster A.F. Kranias G. Alter G. Marovich M. Eller M.A. Dittmer U. Robb M.L. et al.Immunity. 2016; 44 (this issue): 167-178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar report that circulating IL-21-producing CD4+ T cells are phenotypically, transcriptionally, and functionally similar to lymphoid Tfh cells and that such HIV-specific Tfh cells were increased in RV144 trial vaccine recipients. T follicular helper (Tfh) cells provide crucial support to antigen-specific B cells. In this issue of Immunity, Schultz et al., 2016Schultz B.T. Teigler J.E. Pissani F. Oster A.F. Kranias G. Alter G. Marovich M. Eller M.A. Dittmer U. Robb M.L. et al.Immunity. 2016; 44 (this issue): 167-178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar report that circulating IL-21-producing CD4+ T cells are phenotypically, transcriptionally, and functionally similar to lymphoid Tfh cells and that such HIV-specific Tfh cells were increased in RV144 trial vaccine recipients. Follicular T helper (Tfh) cells are a specialized subset of CD4+ T cells that reside in the B cell areas of lymph nodes (i.e., follicles and related germinal centers). Tfh cells provide crucial support to the survival, proliferation, and differentiation of antigen-specific B cells in germinal centers, and, ultimately, to the production of class-switched antibodies that have undergone affinity maturation (Crotty, 2014Crotty S. Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (1147) Google Scholar). The current definition of a Tfh cell includes, in addition to the micro-anatomic criterion, expression of specific phenotypic markers (i.e., CXCR5, PD-1, ICOS, CD200, etc.), production of cytokines such as IL-21, IL-4, and CXCL13, presence of a specific Bcl-6-associated gene expression program, and the ability to induce antibody production by B cells in vitro (Crotty, 2014Crotty S. Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (1147) Google Scholar). Because of their peculiar ability to support the generation of strong antibody responses, Tfh cells are the subject of intense investigation aimed at harnessing this property for novel vaccination approaches as well as immune therapies for infectious diseases and cancer. In the setting of HIV and SIV infections, Tfh cells play a complex immunological and immunopathogenic role: they have been implicated in (1) development of HIV-specific B cell responses, including the production of broadly neutralizing antibodies (bnAbs) that typically require extensive hyper-mutation (Locci et al., 2013Locci M. Havenar-Daughton C. Landais E. Wu J. Kroenke M.A. Arlehamn C.L. Su L.F. Cubas R. Davis M.M. Sette A. et al.International AIDS Vaccine Initiative Protocol C Principal InvestigatorsImmunity. 2013; 39: 758-769Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar, Yamamoto et al., 2015Yamamoto T. Lynch R.M. Gautam R. Matus-Nicodemos R. Schmidt S.D. Boswell K.L. Darko S. Wong P. Sheng Z. Petrovas C. et al.Sci. Transl. Med. 2015; 7: 298ra120Crossref PubMed Scopus (95) Google Scholar); (2) establishment and maintenance of a persistent reservoir of virus-infected cells (Perreau et al., 2013Perreau M. Savoye A.L. De Crignis E. Corpataux J.M. Cubas R. Haddad E.K. De Leval L. Graziosi C. Pantaleo G. J. Exp. Med. 2013; 210: 143-156Crossref PubMed Scopus (480) Google Scholar); and (3) pathogenesis of HIV- or SIV-associated chronic immune activation (Chowdhury et al., 2015Chowdhury A. Del Rio P.M. Tharp G.K. Trible R.P. Amara R.R. Chahroudi A. Reyes-Teran G. Bosinger S.E. Silvestri G. J. Immunol. 2015; 195: 3237-3247Crossref PubMed Scopus (60) Google Scholar). Possibly related to the complex interaction between Tfh cells and HIV is the observation that Tfh cell help to B cells is impaired in HIV-infected individuals, which might contribute to the known difficulty in generating HIV-specific bnAbs (Cubas et al., 2013Cubas R.A. Mudd J.C. Savoye A.L. Perreau M. van Grevenynghe J. Metcalf T. Connick E. Meditz A. Freeman G.J. Abesada-Terk Jr., G. et al.Nat. Med. 2013; 19: 494-499Crossref PubMed Scopus (286) Google Scholar). The concept that Tfh cells are functionally defective during HIV infection and that this “defect” negatively affects the generation of HIV-specific bnAbs provides rationale for interventions aimed at boosting Tfh cell responses (through either direct stimulation of Tfh cell differentiation pathways or blockade of Tfh cell inhibitory pathways) in the setting of HIV prevention or therapy. However, it remains unclear whether and to what extent the HIV-associated Tfh cell dysfunction is a key mechanism responsible for inadequate bnAb production as opposed to being one of the many consequences of the generalized immune deficiency that follows HIV infection. Given the logistical challenges of sampling lymphoid tissues in humans, a substantial scientific effort has been devoted to the characterization of potential peripheral blood counterparts of Tfh cells (peripheral Tfh [pTfh] cells). He et al., 2013He J. Tsai L.M. Leong Y.A. Hu X. Ma C.S. Chevalier N. Sun X. Vandenberg K. Rockman S. Ding Y. et al.Immunity. 2013; 39: 770-781Abstract Full Text Full Text PDF PubMed Scopus (472) Google Scholar showed that peripheral CD4+CXCR5+ T cells include CCR7loPD-1hi “effector” pTfh and CCR7hiPD-1lo “resting” pTfh cells. They proposed that effector pTfh cells are primarily generated in lymphoid tissues but, before they traffic to germinal centers, rapidly differentiate into mature Tfh cells upon antigen re-encounter and represent a biomarker to monitor protective antibody responses during infection or vaccination. In an accompanying study, Locci et al., 2013Locci M. Havenar-Daughton C. Landais E. Wu J. Kroenke M.A. Arlehamn C.L. Su L.F. Cubas R. Davis M.M. Sette A. et al.International AIDS Vaccine Initiative Protocol C Principal InvestigatorsImmunity. 2013; 39: 758-769Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar described pTfh cells as resting CD4+CD45RO+PD-1+CXCR5+CXCR3− T cells that are related to germinal center Tfh cells by gene expression profile, cytokine production, and functional properties. Interestingly, the frequency of these cells was found to correlate with the titer of HIV-specific bnAbs in a large cohort of HIV-infected individuals (Locci et al., 2013Locci M. Havenar-Daughton C. Landais E. Wu J. Kroenke M.A. Arlehamn C.L. Su L.F. Cubas R. Davis M.M. Sette A. et al.International AIDS Vaccine Initiative Protocol C Principal InvestigatorsImmunity. 2013; 39: 758-769Abstract Full Text Full Text PDF PubMed Scopus (641) Google Scholar). In this issue of Immunity, Schultz et al., 2016Schultz B.T. Teigler J.E. Pissani F. Oster A.F. Kranias G. Alter G. Marovich M. Eller M.A. Dittmer U. Robb M.L. et al.Immunity. 2016; 44 (this issue): 167-178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar share their findings regarding pTfh cells during HIV infection. Having postulated that pTfh cells might be identified based on the production of a cardinal cytokine, IL-21 (in analogy to IL-17 for Th17 cells), these authors found that circulating IL-21-producing CD4+ T cells are phenotypically, transcriptionally, and functionally related to lymphoid-tissue-resident Tfh cells (Figure 1). In particular, a complex comparative analysis of the gene expression profile in IL-21-producing CD4+ T cells versus pTfh cells defined based on five different combinations of phenotypic markers revealed that the former are transcriptionally closer to classical Tfh cells than any other studied CD4+ T cell subset. Based on these findings, the authors concluded that a novel definition of pTfh cells based on IL-21 production ex vivo might help identify these cells in various clinical settings and provide a useful monitoring tool for immune-based interventions aimed at selectively boosting Tfh cell function in humans. Intriguingly, Schultz et al., 2016Schultz B.T. Teigler J.E. Pissani F. Oster A.F. Kranias G. Alter G. Marovich M. Eller M.A. Dittmer U. Robb M.L. et al.Immunity. 2016; 44 (this issue): 167-178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar also found that the ALVAC prime, AIDSVAX boost immunization used in the RV144 trial—i.e., the only HIV vaccine to show some hint of efficacy in humans—induced elevated numbers of HIV-specific IL-21-producing pTfh cells. The extent to which these pTfh cells contributed to the relatively minor protective effect against HIV acquisition observed in the RV144 trial remains unknown; several other putative correlates of protection have been identified in the numerous post hoc analyses that have been published in the past several years, including a positive correlation with total HIV-specific CD4+ T cell responses (Lin et al., 2015Lin L. Finak G. Ushey K. Seshadri C. Hawn T.R. Frahm N. Scriba T.J. Mahomed H. Hanekom W. Bart P.A. et al.Nat. Biotechnol. 2015; 33: 610-616Crossref PubMed Scopus (171) Google Scholar). Although less invasive techniques such as fine-needle aspiration (FNA) are being validated in both humans and nonhuman primates as an alternative lymph node sampling method (D. Carnathan, S. Crotty, and G.S., unpublished data), the need for a better understanding of the peripheral blood counterparts of Tfh cells remains important. In this context, several aspects of the biology of pTfh cells remain poorly understood, in particular with respect to their differentiation history, activation status, trafficking potential, and potential for long-term Tfh cell memory (Crotty, 2014Crotty S. Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (1147) Google Scholar). Although the current study by Schultz et al., 2016Schultz B.T. Teigler J.E. Pissani F. Oster A.F. Kranias G. Alter G. Marovich M. Eller M.A. Dittmer U. Robb M.L. et al.Immunity. 2016; 44 (this issue): 167-178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar proposes a potentially useful marker (i.e., IL-21 production) to define pTfh cells in the setting of clinical studies in humans, much more work is needed to fully understand the striking complexity of the Tfh cell universe and the exact physiological role of pTfh cells in supporting the development of class-switched, affinity-matured B cell responses. A key issue in this respect is that the differentiation of Tfh cells appears to be regulated, at a single-cell level, through a complex network of signals (cytokines, chemokines, cell-to-cell contact) that activate or repress transcriptional programs (“differentiation blueprints”) that ultimately define the fate of the CD4+ T cell in becoming a Tfh cell versus another T cell subset (i.e., Th1, Th2, Th17, Treg, etc.) (Crotty, 2014Crotty S. Immunity. 2014; 41: 529-542Abstract Full Text Full Text PDF PubMed Scopus (1147) Google Scholar). This is particularly relevant for IL-21, because multiple types of CD4+ T cells can produce this cytokine. How the peculiar flexibility of the Tfh cell differentiation pathway interfaces with the mechanisms determining the phase(s) in which these cells circulate in peripheral blood as opposed to home to B cell areas of lymph nodes will continue to be the subject of further studies. The work of Schultz et al., 2016Schultz B.T. Teigler J.E. Pissani F. Oster A.F. Kranias G. Alter G. Marovich M. Eller M.A. Dittmer U. Robb M.L. et al.Immunity. 2016; 44 (this issue): 167-178Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar has some interesting implications for the field of AIDS vaccines. In recent years there have been many advances in our understanding of immune responses that might protect against HIV transmission, particularly with respect to the role of HIV-specific bnAbs, which have been identified in the serum of HIV-infected individuals and provide strong protection against virus challenge when passively transferred to macaques (Burton et al., 2012Burton D.R. Poignard P. Stanfield R.L. Wilson I.A. Science. 2012; 337: 183-186Crossref PubMed Scopus (341) Google Scholar). However, the effort to develop immunogens that can robustly elicit these HIV-specific bnAbs in healthy individuals has been so far largely unsuccessful. The observation that most bnAbs have a genetic structure indicating that the producing B cells have undergone repeated rounds of somatic hypermutation as a result of affinity maturation has identified a potential role for Tfh cells, which are key facilitators of these peculiar aspects of the B cell response, in the development of an effective HIV vaccine. Currently, several groups are testing the concept of “Tfh cell adjuvants” (i.e., factors known to promote Tfh cell function in vivo) as components of novel, multi-pronged approaches to AIDS vaccines that might also include next-generation HIV-1 Envelope immunogens, vectors that elicit HIV-specific CD8+ T cell responses, and adjuvants that boost the innate antiviral immune response. This major ongoing effort by the HIV research community will presumably involve, in the next decade or so, a number of both preclinical studies in nonhuman primates and clinical trials in humans that are aimed at testing the safety and efficacy of novel candidate AIDS vaccines that include a Tfh cell enhancing product. For these studies, the proposed identification of circulating, HIV-specific CD4+ T cells that produce IL-21 as (1) the closest relatives of bona fide, lymphoid-tissue-resident Tfh cells and (2) a correlate of efficacy against HIV acquisition in the RV144 trial might provide a significant conceptual and practical advance. The authors thank Shane Crotty for critical review of this manuscript. Circulating HIV-Specific Interleukin-21+CD4+ T Cells Represent Peripheral Tfh Cells with Antigen-Dependent Helper FunctionsSchultz et al.ImmunityJanuary 12, 2016In BriefT follicular helper (Tfh) cells are pivotal for antibody induction. Streeck and colleagues show that HIV-specific Tfh cells circulating in the periphery can be identified by secretion of IL-21 with helper qualities dependent on protein specificity and are found at increased numbers in the moderately protective HIV vaccine trial (RV144). Full-Text PDF Open Archive" @default.
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• W2272264107 title "HIV and Tfh Cells: Circulating New Ideas to Identify and Protect" @default.
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