The nine SLAM family (Slamf) receptors are positive or negative regulators of adaptive and innate immune responses, and of several autoimmune diseases. Here we report that the transfer of Slamf6-/- B6 CD4+ T cells into co-isogenic bm12 mice causes SLE-like autoimmunity with elevated levels of autoantibodies. In addition, significantly higher percentages of Tfh cells and IFN-γ-producing CD4+ cells, as well as GC B cells were observed. Interestingly, the expression of the Slamf6-H1 isoform in Slamf6-/- CD4+ T cells did not induce this lupus-like phenotype. By contrast, Slamf1-/- or Slamf5-/- CD4+ T cells caused the same pathology as WT CD4+ T cells. As the transfer of Slamf [1+6]-/- or Slamf [1+5+6]-/- CD4+ T cells induced WT levels of autoantibodies, the presence of Slamf1 was requisite for the induction of increased levels of autoantibodies by Slamf6-/- CD4+ T cells. We conclude that Slamf6 functions as an inhibitory receptor that controls autoimmune responses.