HLA‐DR Class II expression on myeloid and lymphoid cells in relation to HLA‐DRB1 as a genetic risk factor for visceral leishmaniasis

Genetic variation at HLA‐DRB1 is a risk factor for visceral leishmaniasis (VL) caused by Leishmania donovani. The single nucleotide polymorphism rs9271252 upstream of the DRB1 gene provides a perfect tag for protective versus risk HLA‐DRB1 four‐digit alleles. In addition to the traditional role of the membrane‐distal region of HLA class II molecules in antigen presentation and CD4 T‐cell activation, the membrane‐proximal region mediates ‘non‐traditional’ multi‐functional activation, differentiation, or death signals, including in DR‐expressing T cells. To understand how HLA‐DR contributes to disease pathogenesis, we examined expression at the protein level in circulating myeloid (CD14⁺, CD16⁺) and lymphoid (CD4⁺, CD8⁺, CD19⁺) cells of VL patients (pre‐ and post‐treatment) compared with endemic healthy controls (EHC). Although DR expression is reduced in circulating myeloid cells in active disease relative to EHC and post‐treatment groups, expression is enhanced on CD4⁺ DR⁺ and CD8⁺ DR⁺ T cells consistent with T‐cell activation. Cells of all myeloid and lymphoid populations from active cases were refractory to stimulation of DR expression with interferon‐γ (IFN‐γ). In contrast, all populations except CD19⁺ B cells from healthy blood bank controls showed enhanced DR expression following IFN‐γ stimulation. The rs9271252 genotype did not impact significantly on IFN‐γ‐activated DR expression in myeloid, B or CD8⁺ T cells, but CD4⁺ T cells from healthy individuals homozygous for the risk allele were particularly refractory to activated DR expression. Further analysis of DR expression on subsets of CD4⁺ T cells regulating VL disease could uncover additional ways in which pleiotropy at HLA DRB1 contributes to disease pathogenesis.