Regulatory T cells characterized by low Id3 expression are highly suppressive and accumulate during chronic infection

Abstract

Foxp3+ regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator Id3. Id3lo Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of Id3hi into Id3lo Treg cells and during chronic infection Id3lo Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections.

Cutting Edge: Dynamic Expression of Id3 Defines the Stepwise Differentiation of Tissue-Resident Regulatory T Cells

“…To examine Id3 expression in T R we generated Id3-GFP x Foxp3-mRFP double reporter mice. In agreement with previously published reports, most CD4 + T cells in spleen and lymph nodes (LNs) were Id3 + (16, 18). However, we noted a subset of Id3 - cells in both Foxp3 + T R and Foxp3 - conventional CD4 + T cell populations (Fig 1A).…”

“…In T R , Id3 helps to stabilize Foxp3 through restriction of the E protein E47 and its downstream targets Spi-B and SOCS3 (17). However, Id3 expression is not uniform in T R , and distinct populations of Id3 + and Id3 - have been identified (16, 18). In this study, we show that Id3 is dynamically regulated in T R , and that progressive loss of Id3 correlates with the stepwise differentiation of a highly-functional T R population localized primarily in non-lymphoid tissues.…”

Dynamic expression of Id3 defines the stepwise differentiation of tissue-resident regulatory T cells

“…To examine Id3 expression in T R we generated Id3-GFP x Foxp3-mRFP double reporter mice. In agreement with previously published reports, most CD4 + T cells in spleen and lymph nodes (LNs) were Id3 + (18,20). However, we noted a subset of Id3cells in both Foxp3 + T R and Foxp3conventional CD4 + T cell populations ( Fig 1A).…”

“…In T R , Id3 helps to stabilize Foxp3 through restriction of the E protein E47 and its downstream targets Spi-B and SOCS3 (19). However, Id3 expression is not uniform in T R , and distinct populations of Id3 + and Id3have been identified (18,20). In this study, we show that Id3 is dynamically regulated in T R , and that progressive loss of Id3 correlates with the stepwise differentiation of highly-functional T R population localized primarily in non-lymphoid tissues.…”

Regulatory T cells and T helper 17 cells in viral infection

“…However, during the chronic phase of HIV infection, increased frequency of Tregs may overall have a negative effect on antiviral immune response. Based on the expression level of the transcriptional regulator Id3, Tregs were divided into two subtypes, Id3 lo and Id3 hi Tregs . Id3 hi Tregs could differentiate into Id3 lo Tregs during chronic infection of HIV.…”