A Unique Population of Extrathymically Derived αβTCR+CD4−CD8− T Cells with Regulatory Functions Dominates the Mouse Female Genital Tract

Abstract

A better understanding of the regulatory role of genital tract T cells is much needed. In this study, we have analyzed the phenotype, distribution, and function of T lymphocytes in the female genital tract of naive, pregnant, or Chlamydia trachomatis-infected C57BL/6 mice. Unexpectedly, we found that the dominant lymphocyte population (70–90%) in the genital tract was that of CD3+αβTCRintCD4−CD8− T cells. Moreover, these cells were CD90low but negative for the classical T cell markers CD2 and CD5. The CD3+B220low cells were NK1.1 negative and found in nude mice as well as in mice deficient for MHC class II, β2-microglobulin, and CD1, indicating extrathymic origin. They dominated the KJ126+Vβ8.2+ population in the genital tract of DO11.10 OVA TCR-transgenic mice, further supporting the idea that the CD3+B220low cells are truly T cells. The function of these T cells appeared not to be associated with immune protection, because only CD4+ and CD8+ T cells increased in the genital tract following chlamydial infection. Notwithstanding this, the infected, as well as the uninfected and the pregnant, uterus was dominated by a high level of the CD3+CD4−CD8−B220low cells. Following in vitro Ag or polyclonal stimulation of the CD3+CD4−CD8−B220low cells, poor proliferative responses were observed. However, these cells strongly impaired splenic T cell proliferation in a cell density-dependent manner. A large fraction of the cells expressed CD25 and produced IFN-γ upon anti-CD3 plus anti-CD28 stimulation, arguing for a strong regulatory role of this novel T cell population in the mouse female genital tract.

Donor double‐negative Treg promote allogeneic mixed chimerism and tolerance

“…Others have reported that DN-Treg can down-regulate CD8 + T cell-mediated immune responses in autoimmune and infectious disease models [29,30]. Interestingly, DNTreg, derived from human peripheral blood, possess similar immune-regulatory functions as those we demonstrated [31].…”

MHC class II‐independent CD25+ CD4+ CD8α β+ α β T cells attenuate CD4+ T cell‐induced transfer colitis

“…Although peripheral, competent § g T cell populations in normal mice usually contain almost exclusively SP CD4 + or CD8 + T cells, peripheral 'double negative' (DN) (CD4 -CD8 -) or DP (CD4 + CD8 + ) T cell subsets have been described in mice and man. DN § g T R cells that are derived from murine CD8 + T cells [21,22] can suppress alloresponses [23] or mucosal T cell responses [24]. Virus activation can induce a DP phenotype in human SP CD8 + T cells [25][26][27].…”

Immunity in the female sheep reproductive tract

“…Immunoglobulin A (IgA) and IgG are found in uterine and vaginal secretions [80]. The normal healthy female genital tract harbours few T cells, but infection with Chlamydia trachomatis results in recruitment of CD4+ve and CD8+ve T cells [39]. The same study also found a unique population of T cells in the mouse uterus that appear to perform a regulatory role rather than a protective role.…”

“…Hormones play a very important role in regulating host immunity in the genital tract, distinguishing this from other mucosal sites [39]. There is a vast body of literature on the influence of female hormones on cell populations, antigen presentation and cell function in the reproductive tracts of humans and mice (see [80] for review), but not in sheep.…”

“…These cells are TCRαβ+ve, CD3+ve, CD4-ve, CD8-ve, inhibit proliferation of splenic T cells and are extrathymically-derived, since they are found in nude mice. It is thought that they represent a highly specialised population of T cells with a particular function in the female genital tract, but this remains to be fully defined [39]. They are not the same as conventional CD4+veCD25+ve regulatory T (Treg) cells, key control elements of the adaptive immune response that suppress auto-reactive T cells and prevent inflammation-mediated tissue damage [71].…”