Multicentric Castleman disease is associated with polyfunctional effector memory HHV-8-specific CD8+ T cells

Area of Science:

• Immunology
• Virology
• Oncology

Background:

• Multicentric Castleman disease (MCD) is a severe lymphoproliferative disorder linked to human herpesvirus 8 (HHV-8) in immunocompromised individuals.
• Understanding the immune response, particularly CD8(+) T cells, is crucial for elucidating MCD pathogenesis.

Purpose of the Study:

• To investigate the characteristics of HHV-8-specific CD8(+) T cells in MCD patients compared to asymptomatic HHV-8 carriers (AC).
• To assess the frequency, antigenic repertoire, differentiation, and functional capacity of these T cells.

Main Methods:

• ELISpot assays using 56 peptides from HHV-8 proteins to screen CD8(+) T-cell responses.
• Intracellular cytokine staining (IFN-gamma) and flow cytometry to analyze T-cell phenotypes (CD45RA, CCR7, CD27).
• Correlation analysis between HHV-8 viral load and T-cell populations.

Main Results:

• MCD and AC patients exhibited similar magnitudes and antigenic repertoires of HHV-8-specific CD8(+) T-cell responses.
• A novel HLA-B7-restricted 10-mer epitope in HHV-8 K15 was identified.
• MCD patients showed a distinct T-cell phenotype with significantly more late-differentiated (CD45RA(-)CCR7(-)CD27(-)) and fewer early/intermediate (CCR7(-)CD27(+)CD45RA(-)) effector memory cells compared to AC.
• This phenotypic shift was specific to HHV-8 and not observed for Epstein-Barr virus-specific T cells.
• Higher HHV-8 viral loads negatively correlated with early and intermediate effector memory T cells.
• HHV-8-specific T cells in both groups were polyfunctional, secreting multiple cytokines (IFN-gamma, TNF-alpha, MIP-1beta) and expressing CD107a.

Conclusions:

• MCD pathogenesis is not characterized by a deficiency or functional limitation of HHV-8-specific CD8(+) T cells.
• The differentiation state of these T cells is influenced by HHV-8 viral load.
• These findings provide novel insights into the immune mechanisms underlying MCD.