Hybrid immune cell could contribute to type 1 diabetes autoimmunity
medwireNews: Researchers have discovered an immune cell with the attributes of both B cells and T cells, which is present in increased frequency in some people with type 1 diabetes and capable of activating insulin-specific T-helper cells.
The cells co-expressed the T-cell receptor and the B-cell receptor, along with the CD5 and CD19 markers, and the cells retained both their T-cell and B-cell functions.
“This probably accentuates the autoimmune response because one lymphocyte is simultaneously performing the functions that normally require the concerted actions of two,” lead researcher Abdel-Rahim Hamad (Johns Hopkins University School of Medicine, Baltimore, Maryland, USA) said in a press statement.
Although rare, these hybrid cells were significantly more numerous in people with type 1 diabetes than in those without, leading the researchers, writing in Cell, to suggest that they “could be pathophysiologically important.”
The make-up of the hypervariable regions of the T- and B-cell receptors of these hybrid cells was considerably less varied than seen in T and B cells from people without diabetes.
Strikingly, the complementarity-determining region (CDR3) of the hybrid cell B-cell receptors from three unrelated people with diabetes had identical nucleotide and amino acid sequences. The CDR3 region “denotes the specificity of each clonotype and comprises its antigen binding site,” explain the researchers.
The presence of this one specific clonotype, which they refer to as the “x-clonotype,” in the unrelated people with diabetes “is unlikely to be coincidental given the extreme diversity of [B-cell receptor] repertoire,” they write.
Furthermore, the clonotype was absent from the B cells of a person without diabetes and from public databases of B-cell receptor sequences.
Risk for type 1 diabetes is markedly increased in people with the HLA Class II DQ8 and DQ2 susceptibility alleles. But the researchers note that this “remains paradoxical,” because when insulin peptide is presented to DQ8, it binds poorly, making it a very weak antigen unlikely to trigger a notable T-cell response.
By contrast, the CDR3 peptide on the hybrid cell x-clonotype identified in this study had “optimal anchor residues for binding to DQ8,” making it a highly effective autoantigen. The peptide was able to form stably bound complexes with DQ8 and these were “potent stimulators” of T-helper cells from people with type 1 diabetes who had the HLA-DQ8 susceptibility allele.
“Our findings lay the groundwork for examining whether the x-autoantigen could serve as a [type 1 diabetes] risk biomarker,” say the researchers, stressing that although about 90% of people with type 1 diabetes have DQ8, “only a fraction” of people with DQ8 develop diabetes.
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