In previous work, we found that only 59 (15%) of 396 "autoreactive" T cell clones derived from five patients with lupus nephritis had the ability to selectively augment the production of pathogenic anti-DNA autoantibodies and the majority (49/59) of those autoimmune T helper (Th) clones were CD4+. Surprisingly, 7 of those Th clones were CD4-/CD8- and gamma/delta TCR+, capable of augmenting the production of pathogenic anti-DNA autoantibodies up to 125-fold. The gamma/delta Th clones responded in a MHC-nonrestricted manner to some endogenous autoantigen associated with heat shock proteins (HSP60) on the lupus B cells. The gamma/delta TCR genes expressed by 4 of these Th clones were amplified and sequenced here. Three of the 4 Th clones, each from a different lupus patient, expressed a gene from the V gamma 1 subgroup. Moreover, 2 of the Th clones expressed V delta 5, and the others V delta 1 or V delta 3. These TCRs are rarely expressed by peripheral blood gamma/delta T cells of normal adult humans. The predominant gamma/delta T cells in human peripheral blood express V gamma 2 (V gamma 9) and V delta 2 TCR genes, including HSP-responsive T cells. None of the lupus Th clones expressed this combination of TCR genes. In addition, some of these pathogenic autoantibody-inducing Th clones from the lupus patients had limited diversity and few N-nucleotide additions in their gamma/delta TCR junctional regions (CDR3), thus resembling fetal gamma/delta thymocytes early in ontogeny.