Self-Antigen Prevents CD8 T Cell Effector Differentiation by CD134 and CD137 Dual Costimulation

Self Cite

Cbl-b is an E3 ubiquitin ligase that limits Ag responsiveness in T cells by targeting TCR-inducible signaling molecules. Cbl-b deficiency thus renders T cells hyperresponsive to antigenic stimulation and predisposes individuals toward developing autoimmunity. In part because Cbl-b−/− T cells do not require CD28 costimulation to become activated, and insufficient costimulation is a critical parameter that confers anergy induction over effector differentiation, it has been hypothesized that Cbl-b−/− T cells are resistant to anergy. This possibility has been supported in models in which anergy is normally induced in vitro, or in vivo following exposure to soluble Ag boluses. In the current study, we characterized the response of Cbl-b−/− CD4 T cells in an in vivo system in which anergy is normally induced by a constitutively expressed peripheral self-Ag. Cbl-b expression increased in self-Ag-induced anergic wild-type CD4 T cells, and Cbl-b−/− CD4 T cells underwent more robust proliferation and expansion upon initially encountering cognate self-Ag compared with wild-type counterparts. Nevertheless, both wild-type and Cbl-b−/− CD4 T cells ultimately developed the same impaired ability to respond to antigenic restimulation. The more extensive expansion that occurred during the initial induction of anergy did, however, allow the anergic CD4 T cells to expand to greater numbers when they were functionally resuscitated following replacement of the initial source of tolerizing self-Ag with a viral form of the same Ag.

Section: Discussionsupporting

confidence: 89%

The E3 Ubiquitin Ligase Cbl-b Regulates Expansion but Not Functional Activity of Self-Reactive CD4 T Cells

Rose

Qui²,

Bandyopadhyay³

et al. 2009

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“…Interestingly, the pattern of IFN-γ secretion from acutely activated Clone 4 CD8 T cells is similar to that of cells activated in a tolerizing setting, with LAG + PD-1 int cells producing the most cytokine. Many costimulatory proteins expressed on the surface of lymphocytes are important for CD8 proliferation and effector function, including ICOS and 41-BB (20, 21). We next assessed expression profile of each subset with regards to either ICOS (Fig.…”

Section: Resultsmentioning

confidence: 99%

Functionally Distinct LAG-3 and PD-1 Subsets on Activated and Chronically Stimulated CD8 T Cells

Grosso

Goldberg

Getnet

et al. 2009

235

170

Lymphocyte Activation Gene-3 (LAG-3) is a transmembrane protein that binds MHC class II, enhances regulatory T cell activity, and negatively regulates cellular proliferation, activation, and homeostasis of T cells. Programmed Death 1 (PD-1) also negatively regulates T cell function. LAG-3 and PD-1 are both transiently expressed on CD8 T cells that have been stimulated during acute activation. However, both LAG-3 and PD-1 remain on CD8 T cells at high levels after stimulation within tolerizing environments. Our previous data demonstrated that blockade of either LAG-3 or PD-1 using mAb therapy in combination with vaccination restores the function of tolerized Ag-specific CD8 T cells in models of self and tumor tolerance. It is unclear whether tolerized CD8 T cells coexpress PD-1 and LAG-3 or whether PD-1 and LAG-3 mark functionally distinct populations of CD8 T cells. In this study, we describe three populations of CD8 T cells activated under tolerizing conditions based on LAG-3 and PD-1 staining, each with distinct phenotypic and functional characteristics. From a mechanistic perspective, both Ag concentration and proinflammatory signals control the expression of LAG-3 and PD-1 phenotypes on CD8 T cells under activating and tolerizing conditions. These results imply that signaling through the PD-1 and LAG-3 pathways have distinct functional consequences to CD8 T cells under tolerizing conditions and manipulation of both Ag and cytokine signaling can influence CD8 tolerance through LAG-3 and PD-1.

“…Similar to other costimulatory agonist combinations (29), costimulation with CD134 plus CD137 (dual costimulation) acts synergistically to elicit robust CD8 T cell effector and tumoricidal activity (30–33). Importantly, dual costimulation also induces cytotoxic CD4 Th1 cells that can directly kill MHC class II + tumors (34) and provide linked-help to CD8 T cells (35, 36). We thus reasoned that a tumor-unrelated helper epitope might augment dual costimulation therapeutic efficacy by helping CD8 T cells responding to cross-presented tumor epitopes (37).…”

Section: Introductionmentioning

confidence: 99%

Tumor-Unrelated CD4 T Cell Help Augments CD134 plus CD137 Dual Costimulation Tumor Therapy

Mittal

Rose

Wang

et al. 2015

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The ability of immune-based cancer therapies to elicit beneficial CD8+ CTL is limited by tolerance pathways that inactivate tumor-specific CD4 helper T cells. A strategy to bypass this problem is to engage tumor-unrelated CD4 helper T cells. Thus, CD4 T cells, regardless of their specificity per se, can boost CD8+ CTL priming so long as the cognate epitopes are linked via presentation on the same dendritic cell. Here, we assessed the therapeutic impact of engaging tumor-unrelated CD4 T cells during dual costimulation with CD134 plus CD137 that not only provide help via the above-mentioned classical linked pathway, but also provide non-linked help that facilitates CTL function in T cells not directly responding to cognate antigen. We found that engagement of tumor-unrelated CD4 helper T cells dramatically boosted the ability of dual costimulation to control the growth of established B16 melanomas. Surprisingly, this effect depended upon a CD134-dependent component that was extrinsic to the tumor-unrelated CD4 T cells, suggesting that the dual-costimulated helper cells are themselves helped by a CD134+ cell(s). Nevertheless, the delivery of therapeutic help tracked with an increased frequency of tumor-infiltrating granzyme B+ effector CD8 T cells and a reciprocal decrease in Foxp3+CD4+ cell frequency. Notably, the tumor-unrelated CD4 helper T cells also infiltrated the tumors, and their deletion several days following initial T cell priming negated their therapeutic impact. Taken together, dual costimulation programs tumor-unrelated CD4 T cells to deliver therapeutic help during both the priming and effector stages of the anti-tumor response.