The Role of Tumor Necrosis Factor-α Reception on Dendritic Epidermal T Cell Activation and Function

Inflammatory responses mediated by the cellular components of epithelial tissues are essential for fighting infection and the wound healing process. Epidermal γδ T cells, also known as dendritic epidermal T cells (DETC), participate in wound healing by producing growth factors, chemokines and cytokines necessary for the proliferation and migration of epithelial cells. Initial DETC activation occurs via the γδ T-cell receptor (TCR). However, a second signal is required for full activation and a third signal is needed to sustain the production of factors needed in functions such as wound repair. Although progress has been made in uncovering signal two, requirements for signal three in DETC and the role that pro-inflammatory cytokines such as TNF-α have on regulating and sustaining DETC function are poorly understood. TNF-α signals through two receptors, tumor necrosis factor receptor 1 and 2 (TNFR1 and TNFR2). These receptors transduce varied responses including cellular apoptosis, cellular survival or inflammatory responses. Our data indicate that some DETC express TNFR1 and/or TNFR2 constitutively and that TNFR2 expression is upregulated in the presence anti-CD3ε. We investigated the impact of TNF-α reception on DETC activation by quantifying cytokine, chemokine and growth factor production from DETC stimulated in the presence or absence of TNF-α. We found that TNF-α does not costimulate DETC during activation, but instead upregulates the production of a specific set of cytokines and chemokines independent of TCR activation. To differentiate the roles of TNFR1 and TNFR2, we blocked either TNFR1 or TNFR2 and compared cytokine and chemokine production by DETC. We found that the requirement for TNFR1 and/or 2 is complicated with some cytokine and chemokine production regulated by one or the other receptor, while some cytokine and chemokine production can occur via either receptor. Together these findings help discern how TNF-α regulates DETC function and activation, which may provide potential targets for improving DETC function in wound repair.