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

Multicentric Castleman disease (MCD) is a devastating human herpesvirus 8 (HHV-8)-related lymphoproliferative disorder that occurs in immunocompromised persons. To determine the role of immune responses in MCD, we studied the frequency, antigenic repertoire, differentiation, and functional profile of HHV-8-specific CD8(+) T cells in MCD patients and in human immunodeficiency virus-coinfected asymptomatic HHV-8 carriers (AC). Screening CD8(+) T-cell responses with ELISpot interferon-gamma (IFN-gamma) assays using 56 peptides on 6 latent and lytic HHV-8 proteins showed that MCD and AC patients had responses of similar magnitude and antigenic repertoire and identified a new 10-mer human leukocyte antigen B7CD8epitope in K15. Intracellular IFN-gamma staining showed significantly more CD45RA(-)CCR7(-)CD27(-) CD8(+)IFN-gamma(+) cells (late phenotype) and significantly fewer CCR7(-)CD27(+)CD45RA(-) cells (early and intermediate phenotype) in MCD than in AC patients. This phenotypic shift was not found for Epstein-Barr virus-specific CD8(+) T cells tested as controls. HHV-8 viral loads were negatively correlated with early and intermediate effector memory cells. HHV-8-specific T cells were polyfunctional (secretion of IFN-gamma, tumor necrosis factor-alpha, macrophage inflammatory protein-1 beta, and/or CD107a) in both MCD and AC patients. In conclusion, MCD is not associated with a lack of HHV-8-specific CD8(+) T cells or limitation of their functional profile. Their differentiation increases with HHV-8 viral load. These results offer new insight into the pathophysiology of MCD.