Mechanisms of IL-23 receptor-mediated pathogenicity in CD4+ T cells

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Project Summary/Abstract This proposal presents a five year research career development program focused on the study of the role of the IL-23 receptor (IL-23R) on CD4+ T cells in cutaneous lupus erythematosus (CLE). The candidate is currently an Instructor in Dermatology at Harvard Medical School in the Department of Dermatology at the Brigham and Women's Hospital. The outlined proposal builds upon the candidate's previous research and clinical experience in molecular and cellular immunology and cutaneous biology by leveraging the use of emerging genomic technologies within Dr. Vijay Kuchroo's, his primary mentor's, laboratory. The proposed experiments and didactic work will position the candidate with a unique set of cross disciplinary skills that will enable him to transition to independence as a physician scientist in autoimmune cutaneous biology. Cutaneous involvement is a major feature of systemic lupus erythematosus (SLE), a systemic autoimmune disease affecting multiple organs, but can also occur in the absence of systemic disease. Cutaneous lupus erythematosus (CLE) significantly impacts patients' quality of life, socioeconomic status, and can result in permanent scarring and dyspigmentation. Therefore, more effective therapies are critically required. However, our current understanding of CLE pathogenesis is limited, making the development of targeted therapies difficult. As a consequence, patient care can be negatively impacted as optimal treatment regimens cannot always be achieved. Therapies can improve the skin, systemic disease, both, or neither. Therefore, it is of critical importance that a better understanding of the basic immunologic underpinnings of CLE pathogenesis be achieved to meet this clinical need. This proposal aims to investigate the role of IL-23R expression on CD4+ T cells in the development of CLE. The proposed project will directly address this vital question while overcoming current limitations in the field. Aim 1 will examine the mechanisms by which the IL-23R confers pathogenicity to CD4+ T cells. Aim 2 tests whether the IL-23R confers pathogenicity to CD4+ T cells, which can then drive spontaneous skin inflammation in a mouse model of lupus erythematosus. Aim 3 leverages cutting edge genomic technologies and analysis to identify novel, transcriptionally distinct, pathogenic CD4+ T lymphocytes in the CLE lesional skin. Taken together, this project combines traditional molecular and cellular approaches with emerging genomic technologies and analysis to address a critically unmet need in cutaneous autoimmune disease.