Expansion of CD4dimCD8+T cells characterizes macrophage activation syndrome and other secondary HLH

• Published in: Blood Vol. 140; no. 3; pp. 262 - 273
• Main Authors: Matteis, Arianna De, Colucci, Manuela, Rossi, Marianna N., Caiello, Ivan, Merli, Pietro, Tumino, Nicola, Bertaina, Valentina, Pardeo, Manuela, Bracaglia, Claudia, Locatelli, Franco, De Benedetti, Fabrizio, Prencipe, Giusi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21-07-2022
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2021013549

CD8+ T-cell activation has been demonstrated to distinguish patients with primary and infection-associated hemophagocytic lymphohistiocytosis (pHLH and iaHLH) from patients with early sepsis. We evaluated the activation profile of CD8+ T cells in patients with various forms of secondary HLH (sHLH), including macrophage activation syndrome (MAS). Flow-cytometry analysis was performed on peripheral blood mononuclear cells isolated from children with inactive systemic juvenile idiopathic arthritis (sJIA, n=17), active sJIA (n=27), MAS in sJIA (n=14), iaHLH (n=7) and with other forms of sHLH (n=9). Compared to patients with active sJIA, in patients with MAS and sHLH of different origins, beside a significant increase in the frequency of CD38high/HLA-DR+CD8+ T cells, we found a significant increase in the frequency of CD8+ T cells expressing the CD4 antigen (CD4dimCD8+ T cells). These cells not only expressed high levels of the activation markers CD38 and HLA-DR, suggesting that they were a subset of CD38high/HLA-DR+ CD8+ T cells, but also of the activation/exhaustion markers CD25, PD1, CD95, and IFNγ. The frequency of CD4dimCD8+ T cells strongly correlated with most of the laboratory parameters of MAS severity and with levels of the MAS biomarkers CXCL9 and IL-18. These findings were confirmed in a prospective replication cohort, in which no expansion of particular TCR Vβ family in CD3+ T cells of sHLH patients was found. Finally, frequency of CD4dimCD8+ but not of CD38high/HLA-DR+ CD8+ T cells, significantly correlated with a clinical severity score. Altogether, our data, showing that CD4dimCD8+T cells are increased in patients with MAS/sHLH and associated with disease severity, strongly support their involvement in MAS/sHLH pathogenesis.