The Immune Regulatory Function of Lymphoproliferative Double Negative T Cells In Vitro and In Vivo

Abstract

Lymphoproliferative (lpr) mice, which lack functional Fas receptor expression and develop autoimmune lymphoproliferative disease, have an accumulation of T cell receptor-αβ+CD4−CD8− (double negative T cells [DNTC]) in the periphery. The function of the accumulating DNTC is not clear. In this study we demonstrate that B6/lpr DNTC can dose dependently kill syngeneic CD8+ and CD4+ T cells from wild-type B6 mice through Fas/Fas ligand interactions in vitro. We also demonstrate that B6/lpr DNTC that are activated and expand in vivo are able to specifically down-regulate allogeneic immune responses mediated by syngeneic Fas+CD4+ and CD8+ T cells in vivo. B6/lpr DNTC that have been preactivated in vivo by infusion of either class I– (bm1) or class II– (bm12) mismatched allogeneic lymphocytes are able to specifically enhance the survival of bm1 or bm12, but not third-party skin allografts when adoptively transferred into naive B6+/+ mice. These findings clearly demonstrate that B6/lpr DNTC have a potent immune regulatory function in vitro and in vivo. They also provide new insights into the mechanisms involved in the development of autoimmune disease in lpr mice.

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].…”

Low‐avidity CD8lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8hi T cell responses to the same antigen

“…It was apparent that these regulatory cells were able to downregulate effector memory T cell delayed-type hypersensitivity responses to HA-1, and were intrinsically anergic to antigen stimulation. The CD8 lo phenotype might represent a stage in the development of regulatory TCR + DNTC, which mediate active immunosuppression after transfusion of donor-specific lymphocytes into a reci-pient mouse [5]. We have previously observed that HY-D b tetramer identifies a population of CD8 + T cells that occupy the lower range of the total CD8 expression in both wild-type male (HY)-grafted and ungrafted female B6 mice [18].…”

“…3c). We also performed a fratricide assay as described in a study by Ford et al [5]. Their study demonstrated that regulatory DNTC were able to kill other CD8 + T cells by a Fas/FasL-dependent mechanism.…”

“…While it is clear that CD4 + CD25 + T cells play a critical role in the control of T cell responses [2,3], studies of CD8 + T cell-mediated regulation have been sparse to date, and have revealed different forms of regulation utilizing both deletional and non-deletional mechanisms [4]. For instance, active immunosuppression by transfusion of donor-specific lymphocytes into a murine TCR transgenic mice induced regulatory TCR + CD4 -CD8 -T cells (double negative T cells, DNTC) population [5]. These T cells induced apoptosis in activated donor-specific CD8 + T cells via a Fas-dependent pathway, but not T cells activated to a third-party alloantigen.…”

“…Indeed, DNTC were found to acquire MHC-allopeptide complexes from APC that were presented on their surface. As a result these DNTC functioned as "killer APC" in conjunction with up-regulated FasL induced by activation [5,6]. In contrast to deletional regulation, a distinct population of CD8 + CD28 -T suppressor (Ts) cells were found to be generated in vitro after multiple rounds of stimulation of human peripheral blood mononuclear cells with allogeneic donor APC or self-APC pulsed with allogeneic peptide [7].…”