Literature Watch Implications for transplantation

Abstract

New studies identify critical pathways involved in the generation of CD4+ TFH cells. New studies identify critical pathways involved in the generation of CD4+ TFH cells. CITATION: Choi YS, Gullicksrud JA, Xing S, Zeng Z, Shan Q, Li F, et al LEF-1 and TCF-1 orchestrate TFH differentiation by regulating differentiation circuits upstream of the transcriptional repressor Bcl6. Nat Immunol 2015; 16: 980–990. CITATION: Xu L, Cao Y, Xie Z, Huang Q, Bai Q, Yang X, et al The transcription factor TCF-1 initiates the differentiation of TFH cells during acute viral infection. Nat Immunol 2015; 16: 991–999. Antibody-mediated rejection is a major source of chronic graft failure for which very few effective interventions exist. De novo generation of donor-specific antibody (DSA) is likely a T cell–dependent process that requires the production of high-affinity, class-switched antibody following development of a germinal center (GC) reaction. Over the last decade a multitude of studies have identified and characterized a specialized CD4+ T cell subset, termed follicular helper T cells (TFH), that provides the necessary signals for optimal B cell help and the initiation of a GC reaction. TFH cells access B cell follicles within secondary lymphoid organs by upregulating expression of C-X-C motif receptor 5 (CXCR5), and migrate toward the germinal center by sensing the CXCR5 ligand CXCL13. TFH cells provide important signals for B cell class-switch recombination, including the surface molecules CD154, ICOS, OX40, and members of the signaling lymphocytic activation molecule (SLAM) family, as well as the cytokines interleukin (IL)-21 and IL-4. How do activated CD4+ T cells make the decision to become TFH? Some elements of the developmental program controlling TFH generation are well understood: the transcription factor Bcl-6 is both necessary and sufficient for induction of the TFH differentiation program, in that Bcl-6-/- animals fail to develop TFH and ectopic expression of Bcl-6 fully reconstitutes TFH differentiation in uncommitted CD4+ T cells. However, the signals leading to Bcl-6 expression following CD4+ T cell activation have been less clear. Now, a pair of new studies identifies two new players in the TFH differentiation program. To determine the genes controlling differentiation of TFH versus classical Th1 cells, Choi et al performed an unbiased transcriptome analysis, and identified expression of both Lef1 and Tcf7 in early TFH in vivo following lymphocytic choriomeningitis virus infection in mice. T cell–specific deletion of both Lef1 and Tcf7, which results in the absence of both lymphoid enhancer-binding factor -1 (LEF-1) and T cell factor-1 (TCF-1), resulted in normal numbers of mature CD4+ T cells, but importantly, these cells failed to differentiate into Bcl-6+ CXCR5+ TFH in vivo. Using an independent T cell–specific conditional knockout of TCF-1, Xu et al found that deletion of TCF-1 alone was sufficient to significantly diminish TFH lineage commitment, and furthermore that TFH cells lacking TCF-1 demonstrate reduced expression of Bcl6, Icos, Cxcr5, Il21 and Il4 compared with wild-type cells. Instead, these TCF-1-/- TFH cells exhibit increased expression of genes associated with other CD4+ T cell subsets (Tbx21, Gzmb, Gata3, Rorc and Foxp3). Taken together, these results suggest that TCF-1 (in some contexts aided by LEF-1) is an important regulator of TFH cell fate that exerts its effect by repressing the differentiation programs of other non-TFH subsets. These results have implications for transplantation in that they identify two new targets that are intimately involved in the generation of the GC reaction, and are therefore likely critical for the development of de novo DSA following transplantation. Therapeutic manipulation of TFH lineage commitment could hold promise as a unique strategy for the prevention of antibody-mediated rejection. Both transcription factors are members of a family of high-mobility–group proteins that function as downstream repressors of the canonical Wnt signaling pathway; both are also expressed in CD8+ T cells, where they are required for optimal formation and function of T cell memory. Furthermore, TCF-1 has been shown to positively regulate expression of IL-17A in CD4+ Th17 cells. Thus, these transcription factors may well represent novel targets for therapeutic manipulation of alloaggressive immune responses following transplantation.