Nuclear factor-?B (NF-?B) is a transcription factor that plays many essential roles in immune responses in vivo, from contributing to the formation of lymph nodes and Peyer's patches to allowing generation and maturation of dendritic cells and controlling development and function of several T cell subsets. Several current immunosuppressive drugs to prevent solid organ transplant rejection, as well as many more in development, inhibit NF-?B as part of their mechanism of action. However, NF-?B is a ubiquitous transcription factor the inhibition of which can cause many severe side effects in different organ systems. In our previous funding period we showed that T cell-restricted inhibition of NF-?B, using transgenic mice that express an NF- ?B super-repressor selectively in T cells (I?B??N-Tg mice), results in permanent acceptance of fully allogeneic cardiac allografts and development of donor-specific tolerance via apoptosis of alloreactive T cells. In these mice, T cell-NF-?B activity is inhibited downstream of several receptors, including the TCR, Toll-like receptors (TLRs) and tumor necrosis factor receptor (TNFR) family members. To determine whether selective inhibition of TCR-NF-?B is sufficient for preventing allograft rejection, we have obtained CARMA1-KO mice that lack an adaptor molecule required for selectively linking the TCR and BCR to NF-?B. Our new results indicate that CARMA1-KO mice permanently accept fully allogeneic cardiac allografts, positioning the CARMA1-NF-?B axis as a very promising therapeutic target for clinical transplantation. Importantly, mice deficient in CARMA1 are an invaluable tool to understand the consequences of inhibition of this pathway on the development and differentiation of T cell subsets. We anticipate that drugs that would target NF-?B selectively in T cells rather than in all cell types may have fewer side effects than current immunosuppressive therapies while having the potential to induce transplantation tolerance. However, before developing such inhibitors, it is important to understand fully the function of TCR-CARMA1-NF-?B activity. Our current results indicate that targeting CARMA1 abolishes the thymic development of natural regulatory T cells (nTregs). Conversely, lack of CARMA1 promotes the differentiation of induced regulatory T cells (iTregs), underscoring CARMA1 as playing opposite functions in the generation of nTregs versus iTregs. Further supporting reciprocal requirements for iTreg and Th17 differentiation, our preliminary results indicate that absence of CARMA1 prevents Th17 differentiation. These results reveal novel functions of the TCR- CARMA1-NF-?B pathway that need to be substantiated mechanistically. The main goal of the current proposal is to define the precise role of CARMA1 and TCR-driven NF-?B in the development/differentiation of T cell subsets in vitro and in transplantation models in vivo.
Specific Aim 1. To determine the mechanisms by which CARMA1 regulates the thymic development of nTregs.
Specific Aim 2. To delineate the role of CARMA1-NF-?B in iTreg versus Th17 differentiation.
We have recently shown that mice lacking CARMA1, an adaptor linking TCR to NF-?B, accept cardiac allografts long-term, suggesting that therapeutic targeting of this pathway may be sufficient for the induction of transplantation tolerance. Preliminary experiments reveal that the CARMA1 deficiency results in inhibition of Th17 and nTreg differentiation whereas it facilitates the generation of iTregs, positioning this molecule as having opposite effects for generation of nTregs versus iTregs. In this application we propose to investigate the mechanisms by which TCR-CARMA1-NF-?B regulates formation of nTregs, iTregs and Th17 cells and how these effects impact allograft fate.
|Evaristo, CÃ©sar; Spranger, Stefani; Barnes, Sarah E et al. (2016) Cutting Edge: Engineering Active IKKÎ² in T Cells Drives Tumor Rejection. J Immunol 196:2933-8|
|Barnes, Sarah E; Wang, Ying; Chen, Luqiu et al. (2015) T cell-NF-ÎºB activation is required for tumor control in vivo. J Immunother Cancer 3:1|
|Evaristo, C; Alegre, M-L (2013) IFN-Î³: The Dr. Jekyll and Mr. Hyde of immunology? Am J Transplant 13:3057-8|
|Molinero, Luciana L; Cubre, Alan; Mora-Solano, Carolina et al. (2012) T cell receptor/CARMA1/NF-ÎºB signaling controls T-helper (Th) 17 differentiation. Proc Natl Acad Sci U S A 109:18529-34|
|Porras, Delia Lozano; Wang, Ying; Zhou, Ping et al. (2012) Role of T-cell-specific nuclear factor ÎºB in islet allograft rejection. Transplantation 93:976-82|
|Alegre, Maria-Luisa; Bromberg, Jonathan S (2012) Literature watch implications for transplantation. The anti-infectious role of the IL-17 pathway. Am J Transplant 12:3|
|Molinero, Luciana L; Alegre, Maria-Luisa (2012) Role of T cell-nuclear factor ÎºB in transplantation. Transplant Rev (Orlando) 26:189-200|
|Alegre, M-L; Molinero, L L (2012) The inside story of dendritic cell immunotherapy. Am J Transplant 12:1363-4|
|Alegre, Maria-Luisa; Fu, Yang-Xin (2011) Attenuation by targeting the B- and T-cell attenuator. Transplantation 92:1075-6|
|Molinero, Luciana L; Miller, Michelle L; Evaristo, CÃ©sar et al. (2011) High TCR stimuli prevent induced regulatory T cell differentiation in a NF-ÎºB-dependent manner. J Immunol 186:4609-17|
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