A number of specific autoimmune diseases, including inclusion body myositis (IBM), primary biliary cholangitis (PBC), and Sjogren’s syndrome (SS), and T cell large granular lymphocytic leukemia (T-LGLL) are highly refractory to immunotherapies and appear to involve highly differentiated cytotoxic T cell mediated tissue injury. Using microarray technology applied to human tissue disease samples, we identified a signature of T cell cytotoxicity coupled with a signature of highly differentiated CD8+ T cell effector memory (TEM) and terminally differentiated effector (TEMRA) cells, and confirmed these signatures through immunohistochemistry and flow cytometry of patient samples. We then applied bioinformatics to identify a therapeutic strategy of targeting these populations of cells for depletion through their surface expression of killer cell lectin-like receptor G1 (KLRG1), demonstrated the correlation of KLRG1 gene expression with T cell cytotoxicity across 28,870 human tissue samples, and validated the presence of KLRG1 on patient tissue infiltrating and blood circulating pathogenic T cells. We furthermore demonstrate that human regulatory T cells lack KLRG1 expression, so that targeted depletion of KLRG1+ cells, unlike broader T cell depletions that deplete regulatory cells using siplizumab, alemtuzumab, daclizumab, or anti-thymocyte globulin, is an improved strategy for targeting cytotoxic T cell mediated autoimmune diseases. We then developed a humanized afucosylated anti-KLRG1 antibody (ABC-008) with potent antibody-dependent cell-mediated cytotoxicity (ADCC) and demonstrated its ability to deplete cytotoxic T cells in non-human primates. Anti-KLRG1 depletion therapy with ABC-008 is a rational strategy for diseases characterized by chronic, refractory expansions of cytotoxic lymphocytes, including IBM, PBC, and T-LGLL.