Cbl-b−/− T Cells Demonstrate In Vivo Resistance to Regulatory T Cells but a Context-Dependent Resistance to TGF-β

Abstract

Cbl-b is an E3 ubiquitin ligase that negatively regulates T cell activation. Cbl-b−/− mice develop spontaneous autoimmunity, and Cbl-b dysregulation has been described in both murine and human autoimmune diseases. Although the mechanisms underlying the development of autoimmunity in Cbl-b−/− mice are not yet clear, we have reported that Cbl-b−/− CD4+CD25− effector T cells (Teffs) are resistant to CD4+CD25+ regulatory T cell (Treg)-mediated suppression in vitro and have suggested that this may be an important mechanism in the development of autoimmunity. To confirm the relevance of this resistance to autoimmune disease, we now show that Cbl-b−/− Teffs are resistant to suppression by Tregs in vivo and that this involves a resistance of truly naive Cbl-b−/− Teffs. Additionally, we show that Cbl-b−/− Tregs are fully functional in vivo, further suggesting that the regulatory abnormalities in Cbl-b−/− mice are related to defects in Teff, not Treg, function. To characterize the relevance of TGF-β sensitivity in Treg resistance, we examined in vivo Th17 generation and report that Cbl-b−/− mice are able to mount a normal Th17 response in vivo. As Cbl-b−/− Teffs have been shown to be insensitive to the suppressive effects of TGF-β in other in vivo models, the present results suggest that Cbl-b−/− Teffs demonstrate a context-dependent sensitivity to TGF-β in vivo. Overall, our results suggest that resistance to Tregs may be a bona fide mechanism underlying autoimmunity and that Cbl-b−/− mice offer unique approaches for studying the interrelationships between Treg function, TGF-β–mediated responses, and the development of autoimmunity.

Reinforcement of cancer immunotherapy by adoptive transfer of cblb‐deficient CD8+ T cells combined with a DC vaccine

“…Deficiency in cblb uncouples T cells from requirement of CD28 co-stimulation as well as it renders T cells resistant to Treg via disruption of the TGF-b pathway, 4 whereas TH17 T-cell generation appears to be preserved. 5 Of note, cblb-deficient animals are resistant to tumor formation in vivo, 6 and ATC of cblb-deficient T cells exerts therapeutic efficacy in tumor bearing immuno-deficient hosts or when using TCR transgenic as well as using non-transgenic T cells. 7,8 In this study, we provide first evidence that a therapeutic adoptive transfer of polyclonal cblb-deficient CD8 + T cells isolated from non-TCR transgenic mice, enables the in vivo selection of tumorantigen-specific T cells by co-application of a dendritic cell (DC) vaccine, whereas in our hands single transfer of polyclonal cblbdeficient CD8 + T cells is not sufficient to delay tumor growth in immuno-competent mice.…”

Modulation of Immune Cell Functions by the E3 Ligase Cbl-b

“…TGF-β secretion by tumor cells and tumor-infiltrating Tregs therefore contributes to immune evasion of tumor cells (70). Cbl-b deficiency renders peripheral CD4 + and CD8 + T cells partially resistant to inhibitory effects exerted by Tregs via disruption of the TGF-β pathway (56, 71–76). The interaction of CD4 + CD25 + regulatory T cells and CD4 + CD25 − effector cells in cblb − /− mice was extensively studied by Wohlfert et al (75), demonstrating normal function of cblb -deficient Tregs, but resistance of cbl-b deficient CD4 + CD25 − T cells to inhibition by either Tregs or soluble TGF-β.…”

Ubiquitous points of control over regulatory T cells

“…Correspondingly, mice lacking functional Cbl-b are prone to T cell hyperactivation and autoimmune disease [24]. Interestingly, while tTregs from these mice develop and function similar to those of wild type mice, effector T cells lacking Cbl-b are resistant to the suppressive function of Tregs [25, 26]. …”