Abstract The mechanisms underlying the crosstalk between the microbiota and the immune system remains largely unknown. We previously established that skin colonization with Staphylococcus epidermidisresults in the induction of T cell responses that control tissue function in a way that both enhances cutaneous immunity and promotes tissue repair. To uncover the molecular determinants of S. epidermidisthat stimulate T cells, we engineered a library of S. epidermidismutants with defined cell envelope alterations. Under physiological cutaneous colonization, we found that S. epidermidiscell envelope mutants elicit marked changes in the composition and function of the T cell populations in the skin. The removal of cell envelope lipoproteins and D-alanylation of teichoic acids almost completely abolished CD8 +T cell induction without significant effect on CD4 +T cell stimulation. Deletion of Tlr2gene also strongly reduced the CD8 +T cell response after S. epidermidiscolonization, while the CD4 +T cell response remained unchanged, a phenotype similar to the elimination of cell envelope lipoproteins and D-alanylation of teichoic acid in S. epidermidis. Furthermore, suprabasal keratinocytes express the highest level of TLR2 among keratinocyte subsets. Together, these results support the notion that the ability of S. epidermidisto induce CD8 +T cells is partially dependent on the host sensing of S. epidermidiswall teichoic acids and lipoprotein through TLR2. Using complementary strategies including novel mice models and imaging, current studies are focusing on deciphering on which cell population(s) TLR2 sensing of S. epidermidismolecular determinants is required for the induction of CD8 +T cell responses.