Cytotoxic T-Lymphocyte–Associated Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1) mediated regulation of mono- and dual functional CD4+ and CD8+ T-cell responses in a chronic helminth infection

Chronic helminth infections are known to be associated with the modulation of antigen-specific T cell responses. Strongyloides stercoralis (Ss) infection is characterized by down modulation of antigen specific Th1 and Th17 responses and up-regulation of Th2 and Th9 responses. Immune homeostasis is maintained partially by negative regulators of T cell activation - CTLA-4 and PD-1, which dampen effector responses during chronic infections. However, their roles in Ss infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T cell responses and examined the frequencies of mono and dual functional Th1/Tc1, Th17/Tc17, Th2/Tc2 and Th9/Tc9 cells in Ss infection in 15 infected individuals stimulated with parasite antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade resulted in significantly enhanced frequencies of mono and dual functional Th1/Tc1 and Th17/Tc17 cells and in contrast, diminished frequencies of mono and dual functional Th2/Tc2 and Th9/Tc9 cells with parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T cell subsets in Ss infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.