Cutting Edge: CD47 Controls the In Vivo Proliferation and Homeostasis of Peripheral CD4+CD25+Foxp3+ Regulatory T Cells That Express CD103

Abstract

Peripheral CD103+Foxp3+ regulatory T cells (Tregs) can develop both from conventional naive T cells upon cognate Ag delivery under tolerogenic conditions and from thymic-derived, expanded/differentiated natural Tregs. We here show that CD47 expression, a marker of self on hematopoietic cells, selectively regulated CD103+Foxp3+ Treg homeostasis at the steady state. First, the proportion of effector/memory-like (CD44highCD62Llow) CD103+Foxp3+ Tregs rapidly augmented with age in CD47-deficient mice (CD47−/−) as compared with age-matched control littermates. Yet, the percentage of quiescent (CD44lowCD62Lhigh) CD103−Foxp3+ Tregs remained stable. Second, the increased proliferation rate (BrdU incorporation) observed within the CD47−/−Foxp3+ Treg subpopulation was restricted to those Tregs expressing CD103. Third, CD47−/− Tregs maintained a normal suppressive function in vitro and in vivo and their increased proportion in old mice led to a decline of Ag-specific T cell responses. Thus, sustained CD47 expression throughout life is critical to avoid an excessive expansion of CD103+ Tregs that may overwhelmingly inhibit Ag-specific T cell responses.

Implication of the CD47 pathway in autoimmune diabetes

“…TCR transgenic mice were at least as efficient as those from CD47-sufficient mice at inhibiting CD4 T cell proliferation, monitored by the extent of CFSE dilution. These results support previous findings demonstrating that neither the quantity nor the function of Tregs is reduced in CD47-deficient non-transgenic mice [42]. Rather, Tregs appear to slowly accumulate with age in CD47-deficient mice [42].…”

“…These results support previous findings demonstrating that neither the quantity nor the function of Tregs is reduced in CD47-deficient non-transgenic mice [42]. Rather, Tregs appear to slowly accumulate with age in CD47-deficient mice [42]. Together, these data suggest that the increased susceptibility to autoimmune diabetes in CD47-deficient mice cannot be attributed to a defect in Treg homeostasis or function.…”

Integrin αEβ7: Molecular Features and Functional Significance in the Immune System

“…Rather, expression of aEb7 by dendritic cells was found to be necessary for Treg function (see below). Van et al [106] showed that CD47 controls the in vivo proliferation and homeostasis of the aEb7 expressing subset of peripheral Tregs. There is also evidence that aEb7 expressing CD8 T cells can be suppressive.…”

Use of SNARF-1 to measure murine T cell proliferation in vitro and its application in a novel regulatory T cell suppression assay

“…On the basis of this experience and our validation of SNARF-1 as a T cell proliferation tracking dye, we went on to develop a suppression assay that would allow the simultaneous measurement of both Treg and Tcon proliferation. Thus, CFSE-stained Tregs were found to mediate potent suppression and apoptosis of SNARF-1-stained Tcons in vitro and underwent proliferation themselves when present in co-cultures with Tcons, despite being anergic when cultured alone; in this regard, the assay recapitulated the propensity of Tregs to proliferate in vivo [48,49]. The Treg proliferation was titratable, increasing with increasing numbers of co-cultured Tcons: we speculate that Tcon-derived growth factors, including IL-2 and other ␥ c cytokines, were able to break the anergy of the Tregs in co-culture.…”