Affinity for self antigen selects Treg cells with distinct functional properties

Abstract

How regulatory T cells (Treg cell) control lymphocyte homeostasis is not fully understood. Here we identify two Treg cell populations with differing degrees of self-reactivity and distinct regulatory functions. Triplehi (GITRhiPD-1hiCD25hi) Treg cell are highly self-reactive and control lympho-proliferation in peripheral lymph nodes. Triplelo (GITRloPD-1loCD25lo) Treg cells are less self-reactive and limit development of colitis by promoting conversion of CD4+ Tconv cells into induced Treg cells (iTreg cells). Although Foxp3-deficient (scurfy) mice lack Treg cells, they contain Triplehi-like and Triplelo-like CD4+ T cells with distinct pathological properties. Scurfy TriplehiCD4+T cells infiltrate the skin whereas scurfy TripleloCD4+T cells induce colitis and wasting disease. These findings indicate that T cell receptor affinity for self-antigens drives the differentiation of Tregs into distinct subsets with non-overlapping regulatory activities.

High self-reactivity drives T-bet and potentiates Treg function in tissue-specific autoimmunity

“…Through the use of conditional TCRα-KO mice, it was recently shown that TCR is essential and is continually required for Treg function; however, it is still unclear whether the level of TCR signaling is proportional to Treg function (17). Several approaches have utilized surrogate markers to distinguish Treg populations with various levels of self-reactivity (22,51). A more recent study used a combination of 3 surface markers to differentiate a population of functional Tregs in models of colitis and immune homeostasis (GITR, CD25, PD-1) (51).…”

Tonic Signals: Why Do Lymphocytes Bother?

“…A recent publication from Ed Palmer’s group [67] demonstrated that expression levels of CD25, PD-1, and GITR reflect populations of Tregs with different degrees of self-reactivity: Triple hi Treg (high expression of all three mentioned markers) had increased CD5 and Nur77-GFP levels compared to Triple lo Tregs (low expression of these markers). Using B3K508 TCR transgenic T cells (that recognize peptides of different affinities), the Palmer group showed that ligands at the threshold of negative selection generate Triple lo cells, whereas very high-affinity peptides select Triple hi cells, suggesting that these two populations differ in their degree of affinity for self.…”

“…These cells are maintained in vivo by self (and not foreign) antigens, as this population persists in antigen free mice , which lack infectious, microbial and dietary antigens. Functionally, self-reactive Tregs (Triple hi ) proliferated more in vivo and were more suppressive than Triple lo cells, whereas these lower affinity cells facilitated the conversion of conventional T cells into iTregs in a colitis model, although the mechnanism underlying this conversion has not yet been identified [67]. Collectively, these data suggest that the degree of self-reactivity in CD4 + conventional T cells, CD8 + T cells, and CD4 + regulatory T cells impacts their functional ability to respond to infection and control immune responses.…”

Age-Dependent Changes in Regulatory T Lymphocyte Development and Function: A Mini-Review

“…Recent data demonstrated that the developing tTreg population is heterogeneous and contains at least two functionally diverse subpopulations. One of them (CD25 low GITR low PD-1 low tTreg) induced the emergence of pTreg that prevented intestinal inflammation [18] . It therefore appears that tTreg and pTreg have overlapping but nonredundant functions in vivo.…”