This study tested the hypothesis that V gamma 3 TCR-bearing T cells are influenced by LCs. V gamma 3 T cells and LCs are located in the epidermis of mice. V gamma 3 T cells represent the main T cell population in the skin epithelium and play a crucial role in maintaining the skin integrity, whereas LCs are professional APCs. Although V gamma 3 T cells and LCs form an interdigitating network in the epidermis, not much is known about their reciprocal influence and/or interdependence. We used two different LC-deficient mouse models, in which LCs are constitutively or inducibly depleted, to investigate the role of LCs in maturation, homeostasis, and function of V gamma 3 T cells. We show that V gamma 3 T cell numbers are unaltered by LC deficiency, and V gamma 3 T cells isolated from LC-deficient mice are phenotypically and upon in vitro stimulation, functionally indistinguishable from V gamma 3 T cells isolated from WT mice based on their cytotoxic potential and cytokine production. Additionally, in vivo skin-wounding experiments show no major difference in response of V gamma 3 T cells to wounding in the absence or presence of LCs. These observations indicate that V gamma 3 T cells develop and function independently of LCs. J. Leukoc. Biol. 90: 61-68; 2011.