Recognition of self-peptides in association with distinct HLA class II alleles by autoreactive CD4+ T cells is central for loss of immunological tolerance leading to autoimmune disease. However, identifying immunodominant self-peptides and characterizing autoreactive T cells is challenging. In this issue of the JCI, Falta et al. identify a disease-associated complementarity-determining region 3β motif specific for beryllium-modified C-C motif ligand 4 (CCL4) and CCL3 self-peptides in patients with chronic beryllium disease (CBD), a granulomatous lung disorder with a known HLA class II allelic association. Detection of these antigen-specific CD4+ T cells by beryllium-pulsed HLA-DP2 tetramers presenting CCL4/CCL3 confirms these autoantigens in humans and mice and enables monitoring in the progress of disease. Detection of autoreactive CD4+ T cells by peptide–MHC class II multimers allows for the detailed characterization of disease-promoting T cells. This knowledge has profound implications for the monitoring and development of targeted therapies in human autoimmune disorders.
Karolin Wieber, Christine L. Zimmer, Michael Hertl
pMHC multimer technology can reveal HLA class II–restricted, autoreactive CD4+ T cells in human autoimmune disorders.