CD8 + T Cells Exhibit an Exhausted Phenotype in Hemophagocytic Lymphohistiocytosis

J Clin Immunol. 2021 Nov;41(8):1794-1803. doi: 10.1007/s10875-021-01109-0. Epub 2021 Aug 14.


Purpose: Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome mainly caused by uncontrolled activation of antigen presenting cells and CD8 T cells. CD8 T cell exhaustion is a known phenomenon in chronic viral infections and cancer. However, the role of T cell exhaustion is not yet identified in HLH in the background of persistent inflammation. So, currently, we have characterized the CD8 T cells using flow cytometry to understand the phenomenon of exhaustion in these cells in HLH.

Methods: We have comprehensively evaluated lymphocyte subsets and characterized CD8 T cells using immunophenotypic markers like PD1, TIM3, LAG3, Ki67, Granzyme B, etc. in a cohort of 21 HLH patients. Effector cytokine secretion and degranulation by CD8 T cells are also studied.

Results: Our findings indicate skewed lymphocyte subsets and aberrantly activated CD8 T cells in HLH. CD8 T cells exhibit significantly increased expression of PD1, TIM3, and LAG3 prominently in primary HLH as compared to controls. PD1 + CD8 T cells express elevated levels of Granzyme B and Ki67. Moreover, CD8 T cells are hypofunctional as evidenced by significantly reduced cytokine secretion and compromised CD107a degranulation.

Conclusion: The study has revealed that CD8 + cytotoxic T lymphocytes from HLH patients exhibited high expression of exhaustion markers with overall impaired function. To the best of our understanding, this is the first report suggesting functional exhaustion of CD8 T cells in both primary and secondary HLH. Future studies to understand the association of exhaustion with disease outcome are needed for its probable therapeutic implementation.

Keywords: Hemophagocytic lymphohistiocytosis; PD1; cytokine secretion; cytotoxic CD8 T lymphocytes; functional exhaustion.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Antigens, CD / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Child
  • Child, Preschool
  • Cytokines / immunology
  • Female
  • Granzymes / immunology
  • Hepatitis A Virus Cellular Receptor 2 / immunology
  • Humans
  • Infant
  • Ki-67 Antigen / immunology
  • Lymphocyte Activation Gene 3 Protein
  • Lymphohistiocytosis, Hemophagocytic / immunology*
  • Male
  • Middle Aged
  • Phenotype
  • Programmed Cell Death 1 Receptor / immunology
  • Young Adult


  • Antigens, CD
  • Cytokines
  • HAVCR2 protein, human
  • Hepatitis A Virus Cellular Receptor 2
  • Ki-67 Antigen
  • MKI67 protein, human
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Granzymes
  • Lymphocyte Activation Gene 3 Protein
  • Lag3 protein, human