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Dwelling on T Cell Fate Decisions

2013; Cell Press; Volume: 153; Issue: 4 Linguagem: Inglês

10.1016/j.cell.2013.04.026

1097-4172

Colleen J. Winstead, Casey T. Weaver,

Immunotherapy and Immune Responses

Defining determinants of T cell fate is central to understanding adaptive immunity and the design of effective vaccines. Tubo et al. demonstrate that intrinsic properties of T cell receptor signaling dictate whether CD4 T cells adopt predominantly type 1 helper or follicular helper T cell phenotypes in response to bacterial or viral infection. Defining determinants of T cell fate is central to understanding adaptive immunity and the design of effective vaccines. Tubo et al. demonstrate that intrinsic properties of T cell receptor signaling dictate whether CD4 T cells adopt predominantly type 1 helper or follicular helper T cell phenotypes in response to bacterial or viral infection. Naive CD4 T cells are multipotential precursors, each bearing a unique T cell antigen receptor (TCR). TCR recognition of peptide-MHCII complexes (pMHCII) expressed on antigen-presenting cells (APCs) in T cell zones of secondary lymphoid tissues initiates rapid clonal expansion and differentiation of naive precursors into distinct effector subsets specialized for defense against different classes of microbes. A major early bifurcation in CD4 T cell responses determines deployment of alternative types of helper function: commitment to classical effector T cells (such as Th1, Th2, or Th17), which emigrate to nonlymphoid tissues to regulate microbicidal actions of innate immune cells at sites of infection, or to T follicular helper (Tfh) cells, which traffic to B cell follicles where they induce germinal center responses that produce antimicrobial antibodies (Crotty, 2011Crotty S. Annu. Rev. Immunol. 2011; 29: 621-663Crossref PubMed Scopus (2026) Google Scholar). In addition to a dominant role for cytokines in specifying these fates, mounting evidence implicates an important role for TCR signal strength. In a tour de force of cellular immunology, Tubo et al., 2013Tubo N.J. Pagán A.J. Taylor J.J. Nelson R.W. Linehan J.L. Ertelt J.M. Huseby E.S. Way S.S. Jenkins M.K. Cell. 2013; 153 (this issue): 785-796Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar in this issue of Cell follow the fates of individual CD4 T cell clones responding to the same pMHCII ligand during infection and find remarkably divergent contributions to Tfh and non-Tfh effector responses that correlate with intrinsic characteristics of TCR signaling. The rarity of naive clonal precursors has, until recently, confounded efforts to delineate natural antimicrobial T cell responses. With a frequency of about one in a million for a given antigenic specificity in the CD4 T cell repertoire, or ∼100 cells, tracking responses of endogenous T cells to a single peptide antigen has proved challenging. Making the task more daunting is interclonal variation in TCR usage by the few naive T cells that recognize the same pMHCII complex. This raises the possibility that clones activated by the same microbial peptide might display disparate responses that program alternative differentiative fates, even if the averaged population response to that antigen is more stereotypical—albeit distinct for different antigens. In the current report, the authors find that, indeed, individual CD4 T cell clones activated by the same pMHCII complex via distinct TCRs favor disparate programming for Tfh and non-Tfh differentiation (Figure 1). This supports models that predict a component of predestination intrinsic to the mechanics by which a T cell's antigenic receptor engages its ligand and reinvigorates longstanding interests in understanding relationships between TCR signaling thresholds and graded responses. The findings represent a culmination of two decades of effort by the Jenkins lab to understand CD4 T cell immunity the hard way—not in a culture dish, but in the tissues where they actually occur. Here, they build on their pioneering pMHCII tetramer-based enrichment techniques to enumerate and phenotype rare antigen-specific CD4 T cells (Moon et al., 2007Moon J.J. Chu H.H. Pepper M. McSorley S.J. Jameson S.C. Kedl R.M. Jenkins M.K. Immunity. 2007; 27: 203-213Abstract Full Text Full Text PDF PubMed Scopus (720) Google Scholar; Pepper et al., 2011Pepper M. Pagán A.J. Igyártó B.Z. Taylor J.J. Jenkins M.K. Immunity. 2011; 35: 583-595Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar). By coupling this to elegant in vivo limiting dilution adoptive transfers, Tubo et al., 2013Tubo N.J. Pagán A.J. Taylor J.J. Nelson R.W. Linehan J.L. Ertelt J.M. Huseby E.S. Way S.S. Jenkins M.K. Cell. 2013; 153 (this issue): 785-796Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar fate-map single CD4 T cells from the endogenous response to an infection by attenuated Listeria monocytogenes (Lm) strains engineered to express a variety of model antigens. This intracellular bacterial pathogen is eliminated by coordinated CD4 and CD8 responses, the CD4 T cell arm of which is characterized by parallel Th1-type effector and Tfh differentiation that promotes enhanced microbicidal actions of macrophages and B cell help, respectively. Results from the current study complement and extend a remarkable antecedent study that tracked the developmental fate of single TCR transgenic CD8 T cells following adoptive transfer. Also employing Lm as a model pathogen, Stemberger et al., 2007Stemberger C. Huster K.M. Koffler M. Anderl F. Schiemann M. Wagner H. Busch D.H. Immunity. 2007; 27: 985-997Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar unequivocally demonstrated that a full range of effector and memory progeny arise from individual naive precursors responding to infection (Stemberger et al., 2007Stemberger C. Huster K.M. Koffler M. Anderl F. Schiemann M. Wagner H. Busch D.H. Immunity. 2007; 27: 985-997Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar). Because their study examined a single clonal specificity, however, Stemberger et al., 2007Stemberger C. Huster K.M. Koffler M. Anderl F. Schiemann M. Wagner H. Busch D.H. Immunity. 2007; 27: 985-997Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar could not exclude the possibility that alternative TCR specificities might diverge from this consistent effector/memory pattern. In examining a range of clones reactive to the same antigen and examining the clonal response to multiple antigens, Tubo et al., 2013Tubo N.J. Pagán A.J. Taylor J.J. Nelson R.W. Linehan J.L. Ertelt J.M. Huseby E.S. Way S.S. Jenkins M.K. Cell. 2013; 153 (this issue): 785-796Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar find a remarkable degree of divergence in the contribution of individual clones to the collective effector response to that antigen. This implies that different TCRs expressed by CD4 T cell clones of the same pMHC specificity have intrinsic tendencies to program their progeny for differing ratios of mature subsets—in this case, Th1, Tfh, and germinal center-Tfh cells that develop in response to Lm infection. Similar results are obtained with infection by lymphocytic choriomeningitis virus and are consistent with results of Fazilleau et al., 2009Fazilleau N. McHeyzer-Williams L.J. Rosen H. McHeyzer-Williams M.G. Nat. Immunol. 2009; 10: 375-384Crossref PubMed Scopus (355) Google Scholar, who found that, within a polyclonal population responding to antigen-specific immunization, TCR repertoires of Tfh cells are the most restricted. Thus, all else being equal, variations in TCR signaling imparted by the nature of the TCR's interaction with pMHCII complexes might dictate CD4 T cell fate. So, what is it about the TCR-pMHCII interaction that predicts whether a T cell will favor a Th1 or Tfh fate? Dwell time—that is, the effective half-life a TCR binds its cognate pMHCII ligand so as to fully engage the assembly of downstream signaling components above a threshold, which has been calculated to require on the order of 2 s. Recent experiments that have tested models of TCR-pMHC binding kinetics using systems that more accurately reflect the confinement of the TCR and its pMHC ligand to opposing cell surfaces as occurs in T cell-APC interactions support a variant of the kinetic proofreading model of T cell activation (Huang et al., 2010Huang J. Zarnitsyna V.I. Liu B. Edwards L.J. Jiang N. Evavold B.D. Zhu C. Nature. 2010; 464: 932-936Crossref PubMed Scopus (363) Google Scholar). In this model, serial rebinding to pMHC complexes favored by fast on-rates leads to an aggregate half-life of TCR binding (ta) that can initiate T cell activation despite the brief t1/2 of individual TCR-pMHC binding events. Because they find that the balance of effector cell subsets generated correlates poorly with TCR affinity (KD) as measured by pMHCII tetramer binding, Tubo et al., 2013Tubo N.J. Pagán A.J. Taylor J.J. Nelson R.W. Linehan J.L. Ertelt J.M. Huseby E.S. Way S.S. Jenkins M.K. Cell. 2013; 153 (this issue): 785-796Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar examined ratios of Th1:Tfh:GC-Tfh cells induced by Lm infection using a set of transgenic TCR-pMHCII combinations for which KD and ta values had been previously determined (Govern et al., 2010Govern C.C. Paczosa M.K. Chakraborty A.K. Huseby E.S. Proc. Natl. Acad. Sci. USA. 2010; 107: 8724-8729Crossref PubMed Scopus (109) Google Scholar). Although the relationships prove complex, the results demonstrate much better correlation with aggregate dwell time (ta) than the dissociation constant (KD), making ta a better predictor of CD4 T cell fate and providing support for the notion that higher TCR signal strength favors Tfh over Th1 development (Fazilleau et al., 2009Fazilleau N. McHeyzer-Williams L.J. Rosen H. McHeyzer-Williams M.G. Nat. Immunol. 2009; 10: 375-384Crossref PubMed Scopus (355) Google Scholar). These findings establish that variations in TCR signaling strength can translate to divergent developmental fates at the clonal level (Figure 1). The findings and technical approaches of Tubo et al., 2013Tubo N.J. Pagán A.J. Taylor J.J. Nelson R.W. Linehan J.L. Ertelt J.M. Huseby E.S. Way S.S. Jenkins M.K. Cell. 2013; 153 (this issue): 785-796Abstract Full Text Full Text PDF PubMed Scopus (319) Google Scholar set the stage for more mechanistic studies going forward. What are the "instructions" received by cells with the same TCR specificity that are determined by signal magnitude, and how does this bias between Th1 and Tfh fates? TCR signaling strength positively correlates with asymmetric cell division in naive CD8 T cells that favors alternative fates of daughter cells (King et al., 2012King C.G. Koehli S. Hausmann B. Schmaler M. Zehn D. Palmer E. Immunity. 2012; 37: 709-720Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). If CD4 T cells behave similarly, TCRs that engage pMHCII complexes with greater aggregate dwell times might favor asymmetric cell divisions—with possible implications for Tfh versus non-Tfh effector development. Could asymmetric cell division partition the high-affinity IL-2 receptor component (IL-2Rα, or CD25) between daughter cells and account for its higher expression by developing Th1 cells rather than Tfh cells? And, given that activation of STAT5 by IL-2 receptor signaling favors expression of the transcription factor Blimp-1, which favors the Th1 effector program while repressing Bcl-6 (a transcription factor essential for Tfh development), could TCR signal strength dictate differential programming through this mechanism? What is the relationship, if any, between TCR signal strength and ICOS signaling, which also promotes Tfh development? Finally, what are implications for the quality of the antibody response controlled by Tfh cells or development of CD4 T cell memory? In view of data supporting development of CD4 memory T cells from Tfh precursors (Choi et al., 2013Choi Y.S. Yang J.A. Yusuf I. Johnston R.J. Greenbaum J. Peters B. Crotty S. J. Immunol. 2013; 190: 4014-4026Crossref PubMed Scopus (174) Google Scholar; Pepper et al., 2011Pepper M. Pagán A.J. Igyártó B.Z. Taylor J.J. Jenkins M.K. Immunity. 2011; 35: 583-595Abstract Full Text Full Text PDF PubMed Scopus (320) Google Scholar), does initial TCR signaling serve to direct alternative effector and memory CD4 T cell fates, and if so, might this translate into memory populations with differing recall characteristics? Clearly, much work remains to be done. In the meantime, this study highlights once more the remarkable capacity of naive T cells to integrate a diversity of input gradients from both the TCR and non-TCR receptors to direct alternative programs of differentiation. Single Naive CD4+ T Cells from a Diverse Repertoire Produce Different Effector Cell Types during InfectionTubo et al.CellMay 09, 2013In BriefSingle naive T cells generate distinct ratios of macrophage and B cell helpers, based in part on the strength of signals through their unique TCRs. Full-Text PDF Open Archive