Primary and secondary hemophagocytic lymphohistiocytosis have different patterns of T-cell activation, differentiation and repertoire

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T-cell activation patterns between patients with familial HLH (1 degrees HLH), 2 degrees HLH without apparent infectious trigger (2 degrees HLH) and 2 degrees HLH induced by a viral infection (2 degrees V-HLH). Polyclonal CD8(+) T cells are highly activated in 1 degrees HLH and 2 degrees V-HLH, but less in 2 degrees HLH as assessed by HLA-DR expression and marker combination with CD45RA, CCR7, CD127, PD-1 and CD57. Absence of increased HLA-DR expression on T cells excluded active 1 degrees HLH with high sensitivity and specificity. A high proportion of polyclonal CD127(-)CD4(+) T cells expressing HLA-DR, CD57, and perforin is a signature of infants with 1 degrees HLH, much less prominent in virus-associated 2 degrees HLH. The similar pattern and extent of CD8(+) T-cell activation compared to 2 degrees V-HLH is compatible with a viral trigger of 1 degrees HLH. However, in most 1 degrees HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4(+) T cells indicates that the overall T-cell response in 1 degrees HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants.