T-ing up the storm: pathogenic cycling lymphocytes in the biology of macrophage activation syndrome

Abstract

Background: Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are potentially fatal cytokine storm syndromes with clinical features including fever, pancytopenia, hepatosplenomegaly, coagulopathy, and progressive multiorgan system dysfunction. Mechanistically, HLH / MAS are driven by persistent activation of lymphoid and myeloid cells, but our understanding of the pathogenic cell populations remains incomplete.

Main body: In this Perspectives article, we provide an overview of the biology of HLH / MAS and the critical role of interferon-g in disease pathogenesis. We discuss the recent discovery of cycling lymphocytes in HLH / MAS marked by expression of CD38 and HLA-DR, which are primary producers of IFN-γ. The expansion of cycling lymphocytes correlates with disease activity and helps to distinguish HLH / MAS from clinical mimics. We demonstrate an approach to quantify CD38⁺HLA-DR⁺ cycling lymphocytes and evaluate their utility as a diagnostic biomarker for HLH / MAS. Lastly, we discuss the treatment of MAS, including potential therapeutic options to target these pathogenic lymphocytes.

Conclusion: Understanding of biology of cycling lymphocytes in HLH / MAS will facilitate the development of novel therapeutic approaches to overcome these fatal hyperinflammatory disorders.

Keywords: Hemophagocytic lymphohistiocytosis; Macrophage activation syndrome; T lymphocytes.

Fig. 1

Schematic illustrating the causes of HLH / MAS and the role of various immune cell subsets in driving the cytokine storm. Infections, malignancies, medications, genetic defects in cytolysis, and inflammatory diseases are known triggers of HLH / MAS that lead to immune hyperactivation and cytokine storm. Critical immune cells include lymphocytes, macrophages, and antigen-presenting cells interact to drive the activation and expansion of pathogenic lymphocytes that produce IFN-γ. IFN-γ activates macrophages to produce other cytokines and chemokines to amplify the inflammatory cascade. *SH2D1A and XIAP/BIRC4 are associated with primary HLH but these genes are not directly involved in the cytolytic pathway

Fig. 2

Schematic summarizing the recent studies on CD38⁺ HLA-DR⁺ cycling lymphocytes in HLH / MAS. [–11] HLH / MAS is associated with a prominent expansion of CD38⁺HLA-DR⁺CD8⁺ T cells and milder increase of CD4⁺ T lymphocytes and NK cells with similar characteristics. CD38⁺HLA-DR⁺ cycling T cells are highly proliferative and metabolically active based on transcriptomic analysis and they are also prolific producers of IFN-γ, perforin and granzymes. The expansion of these cells correlates with clinical laboratory findings seen in patients with HLH/MAS. IL-15 and IFN-I in combination can induce the differentiation of CD38⁺HLA-DR⁺ lymphocytes in vitro [11]. Other cytokines including IL-2, IL-12, and IL-18 may elicit synergist effects on IFN-γ production. EBV infection can also induce the expansion of CD38⁺HLA-DR⁺ T cells with or without MAS [50, 51].

Fig. 3

Identification and quantification of CD38⁺HLA-DR⁺T cells by flow cytometry. (A) Required and optional antibodies for the detection of CD38⁺HLA-DR⁺ T cells by flow cytometry. Optional antibodies are used to exclude other leukocyte subsets including NK cells (CD56), monocytes (CD14), neutrophils (CD16) and B lymphocytes (CD19). (B) Illustration of gating strategy for CD38⁺HLA-DR⁺ T lymphocytes and typical results from a healthy individual. The percentage of positive cells is shown in boxes. (C) Example of CD38⁺HLA-DR⁺ T cell quantification performed serially in a patient with Still’s disease complicated by MAS