Turning the Tide Against Regulatory T Cells

Regulatory T (Treg) cells play crucial roles in health and disease through their immunosuppressive properties against various immune cells. In this review we will focus on the inhibitory role of Treg cells in anti-tumor immunity. We outline how Treg cells restrict T cell function based on our understanding of T cell biology, and how we can shift the equilibrium against regulatory T cells. To date, numerous strategies have been proposed to limit the suppressive effects of Treg cells, including Treg cell neutralization, destabilizing Treg cells and rendering T cells resistant to Treg cells. Here, we focus on key mechanisms which render T cells resistant to the suppressive effects of Treg cells. Lastly, we also examine current limitations and caveats of overcoming the inhibitory activity of Treg cells, and briefly discuss the potential to target Treg cell resistance in the context of anti-tumor immunity

A cortisone sensitive CD3low subset of CD4+CD8− thymocytes represents an intermediate stage in intrathymic repertoire selection

Two populations of CD4 single positive (SP) thymocytes were found In transgenic mice bearing class l-restricted Mls-1a reactive (Vβ8.1) TCR genes in the absence of the restriction element. CD3high CD4 sp cells were deleted In the presence of Mls-15 and were cortisone resistant, whereas CD3low CD4 SP cells were not deleted In the presence of Mls-1* and were cortisone sensitive. Intravenous transfer of CD3low CD4 SP cells into nude mice resulted in significant peripheral expansion of these cells with apparent upregulation of CD3. These data Indicate that CD3low CD4 SP thymocytes represent an Intermediate stage In the transition from CDSlow double positive (DP) to CD3high SP thymocytes and raise the possibility that these cells may have undergone positive but not negative selection events (at least to Mls-1a). Furthermore the fact that CD3high DP thymocytes were also deleted by Mls-1a in these mice suggests strongly that sensitivity to Mls-1a deletion is dependent upon stage of thymic maturation (as revealed by TCR density) rather than CD4/CD8 phenotyp

Enhanced positive selection of a transgenic TCR by a restriction element that does not permit negative selection

Very little is known about the conformational properties of the MHC molecules that are able to signal positive selection of a given TCR. To try to understand these parameters and to determine whether these requirements are shared with interactions during negative selection and antigen recognition, we have studied selection and antigen recognition of a transgenic TCR (specific for lymphocytic choriomeningitls virus glycoprotein and H-2Db) in the context of two Db mutants, H-2bm13 and H-2bm14. The data showed that the transgenic TCR was not positively selected by the H-2bm14 haplotype but, interestingly, enhanced positive selection was seen in H-2bm13 mice. The transgenic TCR could not be negatively selected In H-2bm13animals persistently infected with the virus (neonatal virus carrier mice), nor could the transgenic TCR be activated by H-2bm13 infected cells in vivo or in vitro. These experiments show that although a TCR may be selected by a mutant MHC molecule, the corresponding viral antigen cannot be recognized in the context of the mutant MHC molecule, as Judged by both negative selection and T cell reactivity in vivo and in vitro. The ‘enhanced' positive selection occurring in the context of Dbm13 suggests that a different conformation of the MHC molecule is able to select the same TCR and also that various TCR-ligand avidities may permit positive selectio

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

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

Chronic viral infection promotes sustained Th1-derived immunoregulatory IL-10 via BLIMP-1

During the course of many chronic viral infections, the antiviral T cell response becomes attenuated through a process that is regulated in part by the host. While elevated expression of the immunosuppressive cytokine IL-10 is involved in the suppression of viral-specific T cell responses, the relevant cellular sources of IL-10, as well as the pathways responsible for IL-10 induction, remain unclear. In this study, we traced IL-10 production over the course of chronic lymphocytic choriomeningitis virus (LCMV) infection in an IL-10 reporter mouse line. Using this model, we demonstrated that virus-specific T cells with reduced inflammatory function, particularly Th1 cells, display elevated and sustained IL-10 expression during chronic LCMV infection. Furthermore, ablation of IL-10 from the T cell compartment partially restored T cell function and reduced viral loads in LCMV-infected animals. We found that viral persistence is needed for sustained IL-10 production by Th1 cells and that the transcription factor BLIMP-1 is required for IL-10 expression by Th1 cells. Restimulation of Th1 cells from LCMV-infected mice promoted BLIMP-1 and subsequent IL-10 expression, suggesting that constant antigen exposure likely induces the BLIMP-1/IL-10 pathway during chronic viral infection. Together, these data indicate that effector T cells self-limit their responsiveness during persistent viral infection via an IL-10-dependent negative feedback loop.This work was supported by an Australian NHMRC Overseas Biomedical Postdoctoral Fellowship (to I.A. Parish); a Yale School of Medicine Brown-Coxe Postdoctoral Fellowship (to I.A. Parish); the Alexander von Humboldt Foundation (SKA2010, to P.A. Lang); a CIHR grant (to P.S. Ohashi); and by the Howard Hughes Medical Institute and NIH grant RO1AI074699 (to S.M. Kaech). P.S. Ohashi holds a Canada Research Chair in Autoimmunity and Tumor immunity

Protein Kinase B Regulates T Lymphocyte Survival, Nuclear Factor κb Activation, and Bcl-XL Levels in Vivo

The serine/threonine kinase protein kinase B (PKB)/Akt mediates cell survival in a variety of systems. We have generated transgenic mice expressing a constitutively active form of PKB (gag-PKB) to examine the effects of PKB activity on T lymphocyte survival. Thymocytes and mature T cells overexpressing gag-PKB displayed increased active PKB, enhanced viability in culture, and resistance to a variety of apoptotic stimuli. PKB activity prolonged the survival of CD4+CD8+ double positive (DP) thymocytes in fetal thymic organ culture, but was unable to prevent antigen-induced clonal deletion of thymocytes expressing the major histocompatibility complex class I–restricted P14 T cell receptor (TCR). In mature T lymphocytes, PKB can be activated in response to TCR stimulation, and peptide-antigen–specific proliferation is enhanced in T cells expressing the gag-PKB transgene. Both thymocytes and T cells overexpressing gag-PKB displayed elevated levels of the antiapoptotic molecule Bcl-XL. In addition, the activation of peripheral T cells led to enhanced nuclear factor (NF)-κB activation via accelerated degradation of the NF-κB inhibitory protein IκBα. Our data highlight a physiological role for PKB in promoting survival of DP thymocytes and mature T cells, and provide evidence for the direct association of three major survival molecules (PKB, Bcl-XL, and NF-κB) in vivo in T lymphocytes

Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance

Using a tumor model of spontaneously arising insulinomas expressing a defined tumor-associated antigen, we investigated whether tumor growth promotes cross-presentation and tolerance of tumor-specific T cells. We found that an advanced tumor burden enhanced cross-presentation of tumor-associated antigens to high avidity tumor-specific T cells, inducing T cell proliferation and limited effector function in vivo. However, contrary to other models, tumor-specific T cells were not tolerized despite a high tumor burden. In fact, in tumor-bearing mice, persistence and responsiveness of adoptively transferred tumor-specific T cells were enhanced. Accordingly, a potent T cell–mediated antitumor response could be elicited by intravenous administration of tumor-derived peptide and agonistic anti-CD40 antibody or viral immunization and reimmunization. Thus, in this model, tumor growth promotes activation of high avidity tumor-specific T cells instead of tolerance. Therefore, the host remains responsive to T cell immunotherapy