CD4+CD25highCD127low/− forkhead box p3 (Foxp3)+ regulatory T cells (Treg cells) possess functional plasticity. Here we describe a higher frequency of T helper type 1 (TH1)-like, interferon-γ (IFN-γ)-secreting Foxp3+ T cells in untreated subjects with relapsing remitting multiple sclerosis (RRMS) as compared to healthy control individuals. In subjects treated with IFN-β, the frequency of IFN-γ+Foxp3+ T cells is similar to that in healthy control subjects. In vitro, human Treg cells from healthy subjects acquire a TH1-like phenotype when cultured in the presence of interleukin-12 (IL-12). TH1-like Treg cells show reduced suppressive activity in vitro, which can partially be reversed by IFN-γ–specific antibodies or by removal of IL-12.

In recent years, the understanding of regulatory T cell (T cell) biology has expanded considerably. Key observations have challenged the traditional definition of T cells and have provided insight into the underlying mechanisms responsible for the development of autoimmune diseases, with new therapeutic strategies that improve disease outcome. This Review summarizes the newer concepts of T cell instability, T cell plasticity and tissue-specific T cells, and their relationship to autoimmunity. Those three main concepts have changed the understanding of T cell biology: how they interact with other immune and non-immune cells; their functions in specific tissues; and the implications of this for the pathogenesis of autoimmune diseases.

TIGIT is a newly identified receptor expressed on T cells that binds to CD155 on the dendritic cell surface driving them to a more tolerogenic phenotype. Given that TIGIT contains an ITIM motif in its intracellular domain and considering the potential importance of the TIGIT/CD226 pathway in human autoimmune disease, we investigated the specific role of TIGIT in human CD4+ T cells. Using an agonistic anti-TIGIT mAb, we demonstrate a direct inhibitory effect on T cell proliferation with a decrease in expression of T-bet, GATA3, IRF4 and RORc with inhibition of cytokine production, predominately IFNγ. Knockdown of TIGIT expression by shRNA resulted in an increase of both T-bet and IFNγ mRNA and protein expression with concomitant decrease in IL-10 expression. Increases in IFNγ with TIGIT knockdown could be overcome by blocking CD226 signaling indicating that TIGIT exerts immunosuppressive effects by competing with CD226 for the same CD155 ligand. These data demonstrate that TIGIT can inhibit T cell functions by competing with CD226 and can also directly inhibit T cells in a T cell intrinsic manner. Our results provide evidence for a novel role of this alternative co-stimulatory pathway in regulating human T cell responses associated with autoimmune disease.