Pathogenic autoantibody-inducing [formula omitted] T helper cells from patients with lupus nephritis express unusual T cell receptors

Abstract

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 γ δ TCR +, capable of augmenting the production of pathogenic anti-DNA autoantibodies up to 125-fold. The γ δ The clones responded in a MHC-nonrestricted manner to some endogenous autoantigen associated with heat shock proteins (HSP60) on the lupus B cells. The γ δ 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 Vγ1 subgroup. Moreover, 2 of the Th clones expressed Vδ5, and the others Vδ1 or Vδ3. These TCRs are rarely expressed by peripheral blood γ δ T cells of normal adult humans. The predominant γ δ T cells in human peripheral blood express Vγ2 (Vγ9) and Vδ2 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 γ δ TCR junctional regions (CDR3), thus resembling fetal γ δ thymocytes early in ontogeny.