Portal de Periódicos da CAPES

Establishing the Follicular Helper Identity

2009; Cell Press; Volume: 31; Issue: 3 Linguagem: Inglês

10.1016/j.immuni.2009.08.017

1097-4180

George Kassiotis, Anne O’Garra,

Immune Response and Inflammation

Among other genes, expression of the Bcl-6 transcriptional repressor distinguishes follicular helper T (Tfh) cells from other helper T cell subsets. In this issue of Immunity, Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar demonstrate that Bcl-6 directs Tfh cell differentiation. Among other genes, expression of the Bcl-6 transcriptional repressor distinguishes follicular helper T (Tfh) cells from other helper T cell subsets. In this issue of Immunity, Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar demonstrate that Bcl-6 directs Tfh cell differentiation. The immune system of higher vertebrates has a remarkable ability to identify the particular order or even class of invading microorganisms and tailor its response accordingly. Distinct subsets of helper T (Th) cells are induced by different pathogens, characterized by unique sets of effector function and migration pattern. The phenotype of each Th cell subset is the result of distinctive gene expression profiles, established by selective expression of master regulators (Zhou et al., 2009Zhou L. Chong M.M. Littman D.R. Immunity. 2009; 30: 646-655Abstract Full Text Full Text PDF PubMed Scopus (1036) Google Scholar). Since their original description by Mosmann and Coffman, Th1 and Th2 cell subsets have been shown to differentiate under the control of the transcription factors T-bet and GATA-3, respectively (Zhou et al., 2009Zhou L. Chong M.M. Littman D.R. Immunity. 2009; 30: 646-655Abstract Full Text Full Text PDF PubMed Scopus (1036) Google Scholar). In more recent years, regulatory T (Treg) cells and Th17 cells have been recognized as separate subsets, whose development is controlled by the transcription factors FoxP3 and RORγt, respectively (Zhou et al., 2009Zhou L. Chong M.M. Littman D.R. Immunity. 2009; 30: 646-655Abstract Full Text Full Text PDF PubMed Scopus (1036) Google Scholar). Follicular helper T (Tfh) cells are another distinguishable subset of Th cells, specialized in providing help for B cell responses. After priming by antigen-presenting dendritic cells (DCs) in the T cell zone of secondary lymphoid organs, a fraction of effector Th cells migrate toward the B cell follicle, where they interact with antigen-presenting B cells. Migration of Tfh cells into the B cell follicle is governed to a large extent by regulated chemokine receptor expression, namely upregulation of CXCR5 and CXCR4 and downregulation of CCR7 (Fazilleau et al., 2009aFazilleau N. Mark L. McHeyzer-Williams L.J. McHeyzer-Williams M.G. Immunity. 2009; 30: 324-335Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). In addition to antigen presented by B cells and recognized by the T cell receptor (TCR), productive interaction between Tfh cells and B cells is mediated by an array of accessory molecules, including CD40L, OX40, and ICOS on Tfh cells and CD40, OX40L, and ICOSL on B cells (Fazilleau et al., 2009aFazilleau N. Mark L. McHeyzer-Williams L.J. McHeyzer-Williams M.G. Immunity. 2009; 30: 324-335Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar). This interaction is required for subsequent generation of both plasma cells and germinal center (GC) B cells, which is tightly controlled by the cytokine secretion profile of Tfh cells. Although Tfh cells display a unique differentiation program, no master transcription factor responsible for initiating and maintaining this program had been identified. Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar in this issue of Immunity and two other studies published in Science (Johnston et al., 2009Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. Dent A.L. Craft J. Crotty S. Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1019) Google Scholar, Nurieva et al., 2009Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. Wang Y.H. Dong C. Science. 2009; 325: 1001-1005Crossref PubMed Scopus (968) Google Scholar) demonstrate that the Tfh cell differentiation program is controlled by B cell lymphoma 6 (Bcl-6). Bcl-6 is a transcriptional repressor, and its absence leads to defective GC formation and induction of T cell-dependent antibody responses, in addition to an ultimately fatal inflammatory syndrome. Among Th cell subsets, Tfh cells display selective expression of Bcl-6, which was suggestive of a potential involvement of Bcl-6 in Tfh cell generation. However, cell-intrinsic control of GC B cell differentiation by Bcl-6 had masked, until now, the role for Bcl-6 in Tfh cell differentiation. With different but complementary approaches to address the role of Bcl-6 specifically in T cells, the three new studies clearly demonstrate that T cell-specific deficiency in Bcl-6 prevents the generation of Tfh cells and subsequently the formation of GC and production of antibodies (Johnston et al., 2009Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. Dent A.L. Craft J. Crotty S. Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1019) Google Scholar, Nurieva et al., 2009Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. Wang Y.H. Dong C. Science. 2009; 325: 1001-1005Crossref PubMed Scopus (968) Google Scholar, Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). Th cells lacking Bcl-6 failed to express Tfh cell-related markers upon activation in vitro or in vivo. In contrast, differentiation of Th1, Th2, and Th17 cell subsets was enhanced in the absence of Bcl-6. Of interest, Bcl-6 deficiency also reduced the generation of FoxP3+ Treg cells in response to TGF-β signaling, and this reduction was partly due to enhanced Th1 and Th2 cell differentiation of Bcl-6-deficient Th cells (Nurieva et al., 2009Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. Wang Y.H. Dong C. Science. 2009; 325: 1001-1005Crossref PubMed Scopus (968) Google Scholar). The new studies also demonstrate that constitutive overexpression of Bcl-6 in Th cell precursors was sufficient to induce expression of Tfh cell-related genes, including those that encode CXCR5, CXCR4, PD-1, and ICOS (Figure 1). At the same time, Bcl-6 overexpression directly inhibited the differentiation of Th1, Th2, and Th17 cell subsets. The mechanism underlying inhibition of Th1, Th2, and Th17 cell differentiation by Bcl-6 involves its transcriptional repressor activity. Indeed, similar to the reported repression of the Th2 cell regulator GATA-3 (Kusam et al., 2003Kusam S. Toney L.M. Sato H. Dent A.L. J. Immunol. 2003; 170: 2435-2441PubMed Google Scholar), Bcl-6 was found to bind directly to the promoters of the human TBX21 and RORC genes, encoding T-bet and RORγt, respectively, suggesting that Bcl-6 may repress their transcription (Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). However, direct transcriptional repression by Bcl-6 overexpression could be demonstrated only for Tbx21 and Gata3 (Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar), whereas Bcl-6 overexpression inhibited the activity, but not the expression, of RORγt (Nurieva et al., 2009Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. Wang Y.H. Dong C. Science. 2009; 325: 1001-1005Crossref PubMed Scopus (968) Google Scholar). Nevertheless, the DNA-binding activity of Bcl-6 was critical for repression of either expression or activity of all three Th1, Th2, and Th17 cell master transcription factors (Nurieva et al., 2009Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. Wang Y.H. Dong C. Science. 2009; 325: 1001-1005Crossref PubMed Scopus (968) Google Scholar). The transcriptional repressor activity of Bcl-6 is seemingly difficult to connect mechanistically with induction of Tfh cell-specific genes. It could be that the Tfh differentiation program is the default pathway for activated Th cell precursors when all other alternative pathways are blocked by the action of Bcl-6. However, Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar further show that Bcl-6 also repressed expression of several clusters of small single-stranded RNAs, collectively known as microRNAs (miRNAs), which are involved in posttranscriptional repression of target mRNAs. Specificity of miRNA-mediated repression is provided by complementarity between the miRNA and parts of the target mRNA and several miRNAs can target the same mRNA. Interestingly, clusters of miRNAs repressed by Bcl-6 included those that target the mRNA encoding CXCR5, CXCR4, or PD-1 for degradation (Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). Furthermore, Bcl-6 represses two miRNAs, which have been previously implicated in repression of ICOS (Yu et al., 2007Yu D. Tan A.H.-M. Hu X. Athanasopoulos V. Simpson N. Silva D.G. Hutloff A. Giles K.M. Leedman P.J. Lam K.P. et al.Nature. 2007; 450: 299-303Crossref PubMed Scopus (329) Google Scholar). Although Yu et al. did not report upregulation of ICOS in Bcl-6-overexpressing Tfh cells, Bcl-6 overexpression did result in elevated ICOS expression in Tfh cells responding in vivo to a viral infection (Johnston et al., 2009Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. Dent A.L. Craft J. Crotty S. Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1019) Google Scholar). Therefore, several Tfh-related genes may be indirectly induced by Bcl-6, via release from miRNA-mediated repression (Figure 1). Although Bcl-6 repressed the key cytokines associated with Th1, Th2, or Th17 cell differentiation, it did not affect the production of IL-2 and IL-21. Both of these cytokines are shared by other Th cell subsets as well, and they can promote the growth of both T and B cells. Despite strong repression of IFN-γ, IL-17, and IL-4 production by Bcl-6, Tfh cells may still produce low amounts of these cytokines. A substantial fraction of Tfh cells generated in response to viral infection produced IFN-γ (Johnston et al., 2009Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. Dent A.L. Craft J. Crotty S. Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1019) Google Scholar), and IL-4 production was found in Tfh cells induced by parasitic infection (Reinhardt et al., 2009Reinhardt R.L. Liang H.E. Locksley R.M. Nat. Immunol. 2009; 10: 385-393Crossref PubMed Scopus (529) Google Scholar). Importantly, production of Th1 or Th2 cell cytokines by Tfh cells appears to be vital for directing the appropriate switching of immunoglobulin class (Reinhardt et al., 2009Reinhardt R.L. Liang H.E. Locksley R.M. Nat. Immunol. 2009; 10: 385-393Crossref PubMed Scopus (529) Google Scholar). Furthermore, the overlap in cytokine production may reflect shared or sequential steps in the differentiation pathways of Tfh and other Th cell subsets. Indeed, Bcl-6 overexpression in Th cells that had begun their Th1 or Th17 cell polarization diverted them into the Tfh cell lineage (Yu et al., 2009Yu D. Rao S. Tsai L.M. Lee S.K. He Y. Sutcliffe E.L. Srivastava M. Linterman M. Zheng L. Simpson N. et al.Immunity. 2009; 31 (this issue): 457-468Abstract Full Text Full Text PDF PubMed Scopus (794) Google Scholar). It is possible that all Tfh cells start life as another Th cell subset (Figure 1). One important question that arises is whether or not, once assumed, the Tfh cell differentiation profile is stable. Moreover, if the Tfh state of differentiation is stable, the fate of Tfh cells after resolution of the immune response or during chronic infection will be an important element to determine. Given the vital role for Bcl-6 in driving the Tfh differentiation program, another question that arises is what induces Bcl-6 expression in activated Th cell precursors. Previous and current work by Nurieva et al., 2008Nurieva R.I. Chung Y. Hwang D. Yang X.O. Kang H.S. Ma L. Wang Y.H. Watowich S.S. Jetten A.M. Tian Q. Dong C. Immunity. 2008; 29: 138-149Abstract Full Text Full Text PDF PubMed Scopus (865) Google Scholar, Nurieva et al., 2009Nurieva R.I. Chung Y. Martinez G.J. Yang X.O. Tanaka S. Matskevitch T.D. Wang Y.H. Dong C. Science. 2009; 325: 1001-1005Crossref PubMed Scopus (968) Google Scholar has revealed that Bcl-6 is induced by IL-6 and IL-21, but inhibited by TGF-β. The action of Bcl-6 was also antagonized by Blimp-1, and expression of Blimp-1 was repressed by Bcl-6 (Johnston et al., 2009Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. Dent A.L. Craft J. Crotty S. Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1019) Google Scholar), analogous with the interplay of Bcl-6 and Blimp-1 in GC B cells. Tfh cell differentiation, and by extension Bcl-6 expression, was also influenced by interaction of ICOS-expressing Th cells with ICOSL-positive B cells (Nurieva et al., 2008Nurieva R.I. Chung Y. Hwang D. Yang X.O. Kang H.S. Ma L. Wang Y.H. Watowich S.S. Jetten A.M. Tian Q. Dong C. Immunity. 2008; 29: 138-149Abstract Full Text Full Text PDF PubMed Scopus (865) Google Scholar), and ICOS overexpression alone is sufficient to drive excessive Tfh cell differentiation (Yu et al., 2007Yu D. Tan A.H.-M. Hu X. Athanasopoulos V. Simpson N. Silva D.G. Hutloff A. Giles K.M. Leedman P.J. Lam K.P. et al.Nature. 2007; 450: 299-303Crossref PubMed Scopus (329) Google Scholar). Moreover, Johnston et al., 2009Johnston R.J. Poholek A.C. DiToro D. Yusuf I. Eto D. Barnett B. Dent A.L. Craft J. Crotty S. Science. 2009; 325: 1006-1010Crossref PubMed Scopus (1019) Google Scholar reported a near-complete absence of Tfh cells in mice lacking antigen-specific B cells and antibodies. Similarly, B cells have been shown to play a vital role in the acquisition of the Tfh cell phenotype, but not the loss of FoxP3 expression, during conversion of committed Treg cells into Tfh cells in gut Peyer's patches (Tsuji et al., 2009Tsuji M. Komatsu N. Kawamoto S. Suzuki K. Kanagawa O. Honjo T. Hori S. Fagarasan S. Science. 2009; 323: 1488-1492Crossref PubMed Scopus (457) Google Scholar). However, Th cell accumulation into the B cell follicle is thought to be independent of cognate interaction with B cells. Furthermore, SAP deficiency in Th cells prevents prolonged contact of Th cells with follicular B cells and entry into the GC, but does not prevent expression of CXCR5 and ICOS or follicular localization (Qi et al., 2008Qi H. Cannons J.L. Klauschen F. Schwartzberg P.L. Germain R.N. Nature. 2008; 455: 764-769Crossref PubMed Scopus (440) Google Scholar). These findings would suggest that early Tfh cell differentiation is initiated by antigen-presenting DCs and that the full or permanent Tfh cell profile is acquired after successful interaction with follicular and GC B cells. Lastly, a recent report has associated Tfh differentiation with higher-than-average TCR affinity for antigen-MHC class II complexes (Fazilleau et al., 2009bFazilleau N. McHeyzer-Williams L.J. Rosen H. McHeyzer-Williams M.G. Nat. Immunol. 2009; 10: 375-384Crossref PubMed Scopus (329) Google Scholar), although the type of the antigen-presenting cell that mediates this TCR affinity selection process remains unclear. Precisely how all these diverse signals are integrated in Th precursors to induce Tfh differentiation will require further investigation. Not only does the important finding that Bcl-6 directs Tfh cell differentiation firmly establish that Tfh cells are a separate subset of Th cells, it also provides a better means of identifying Tfh cells. Entry into B cell follicles may not be an exclusive privilege of Tfh cells, and not all Tfh cells are found in B cell follicles. Furthermore, the phenotype of Tfh cells is unique among Th cells only in the degree in which a combination of markers are expressed. This overlap in phenotype between Th subsets has hindered accurate identification of Tfh cells. Just as the use of FoxP3 has revolutionized the delineation of Treg cells, the use of Bcl-6 as a molecular marker will undoubtedly facilitate the study of Tfh cells. The Transcriptional Repressor Bcl-6 Directs T Follicular Helper Cell Lineage CommitmentYu et al.ImmunityJuly 23, 2009In BriefFollicular helper T (Tfh) cells provide selection signals to germinal center B cells, which is essential for long-lived antibody responses. High CXCR5 and low CCR7 expression facilitates their homing to B cell follicles and distinguishes them from T helper 1 (Th1), Th2, and Th17 cells. Here, we showed that Bcl-6 directs Tfh cell differentiation: Bcl-6-deficient T cells failed to develop into Tfh cells and could not sustain germinal center responses, whereas forced expression of Bcl-6 in CD4+ T cells promoted expression of the hallmark Tfh cell molecules CXCR5, CXCR4, and PD-1. Full-Text PDF Open Archive