Low‐avidity CD8^lo T cells induced by incomplete antigen stimulation in vivo regulate naive higher avidity CD8^hi T cell responses to the same antigen

Abstract

We have previously reported that multiple injections of soluble MHC class I tetramers assembled with wild-type HY peptide induces unresponsiveness to male skin grafts in naive female C57BL/6 (B6) mice. Induction of unresponsiveness is dependent on a population of unresponsive allospecific CD8 lo T cells. Reduced expression of CD8 acts to limit a T cell response to HY peptide by limiting the avidity window of effective signal transduction. We and others have demonstrated that CD8 lo T cells are an alternative stable phenotype of CD8ab + T cells in vitro and in vivo after antigen stimulation. We show here that CD8 lo T cells can suppress naive CD8 + T cell responses to HY antigen in vitro and male skin graft rejection in vivo after adoptive transfer into female recipients. These novel regulatory T cells express surface TGF-b1 and secrete T cytotoxic 2 cytokines after antigen-specific stimulation. Anti-TGF-b antibody and latency-associated peptide inhibit the suppressive effects in vitro. We also show that HY-specific memory CD8 + T cells overcome regulation by CD8 lo T cells. These data define a novel peripheral regulatory CD8 + T cell population that arises after repeated antigen encounter in vivo. These cells have implications in the maintenance of tolerance and memory.See accompanying commentary http://dx.doi.org/10.1002/eji200535797 IntroductionDuring the past few years, mechanisms of regulation of T cell activity have attracted much attention. There has been a resurgence of interest in regulatory T cells in autoimmunity, and more recently, harnessing their potential as a means to prevent graft rejection [1], albeit largely unsuccessful to date. 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. It appears that these regulatory T cells require antigen-specific recognition. 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]. Interestingly, such cells suppressed CD4 + T cells responses and induced regulatory CD4 + CD25 + T cells. Immunoregulation was dependent on th...

Induced peripheral regulatory T cells: The family grows larger

“…An alternative possibility is that the diversity in experimental models and approaches used to study Treg by different investigators has hampered the identification of a more homogenous set of mechanisms that control peripheral Treg function; however, when viewed from an evolutionary perspective, the diversity in phenotype and function of peripherally induced Treg makes sense: nature simply takes every measure it can to secure physiological processes that lie at the heart of life itself. The prediction from this view is that with the findings of Maile et al [22], we have not seen the last Treg to emerge in the literature. On the contrary, more immunoregulatory cells are likely to be discovered, not only in the T cell compartment, but also in other cells of importance, e.g.…”

“…A report in the present issue of the European Journal of Immunology by Maile et al [22] describes the identification of CD8 + Treg that arise after stimulation with peptide-loaded MHC class I tetramers in vivo. In a paper published previously, Maile et al demonstrated that repeated injections of MHC class I tetramers (H-2D b ) loaded with an HY peptide into female HY TCR transgenic mice led to functional unresponsiveness against male grafts [23].…”

“…While the study by Maile et al [22] addresses, and answers, many important problems, there are also additional questions that arise from the study, e.g. the way in which the HY tetramers "select" the CD8 low T cells, and the types of Treg-inducing events which occur in normal immune reactions that the HY tetramer stimulations may possibly mimic.…”

Availability of a Diversely Avid CD8+ T Cell Repertoire Specific for the Subdominant HLA-A2-Restricted HIV-1 Gag p2419–27 Epitope

“…All of the TV9-specific clonotypes, including those with the lowest avidities, expressed similar levels of CD8 as determined by immunostaining and produced Tc1-type cytokines. Thus, TV9 does not appear to elicit CD8 low regulatory T cells generated by suboptimal restimulations (93). Although CD8 participation enabled low-avidity T cells to proliferate as rapidly as their high-avidity counterpart and persist in these cultures, ligation of CD8 was insufficient to overcome low avidity for activation of some downstream effector functions, such as the suppression of virus replication.…”

Naturally acquired tolerance and sensitization to minor histocompatibility antigens in healthy family members

“…17,18 Low avidity CD8 dim staining HY-specific T REG have been described in a murine allograft tolerance model. 30 These observations collectively point to incomplete T-cell receptor signaling as a common feature of T REG function. This phenotypic characteristic can however not be used for identification of minor H antigen-specific T REG because some tetramer dim staining fractions also contained minor H antigen-specific T CTL .…”