PD-1 expression defines two distinct T-cell sub-populations in follicular lymphoma that differentially impact patient survival

To determine the biological and clinical relevance of programmed death 1 (PD-1) in follicular lymphoma (FL), we characterized PD-1(+) T-cell subsets and assessed their biological function as well as potential clinical impact. We found that PD-1 is expressed on intratumoral CD4(+) T cells with both bright and dim intensity, representing two different sub-populations of cells. By immunohistochemistry, we found that CD4(+)PD-1(high) T cells predominantly reside in the lymph node follicles, while PD-1(low) T cells are mainly located in an interfollicular pattern. Intratumoral CD4(+)PD-1(high) T cells have a T(FH) cell phenotype, express CXCR5, secrete IL-21 and are BCL-6 positive with no TIM-3 expression. In contrast, CD4(+)PD-1(low) T cells have an exhausted phenotype, express TIM-3 and do not express BCL-6 and CXCR5. Functionally, CD4(+)PD-1(high) T cells actively supported B-cell growth, while CD4(+)PD-1(low) T cells displayed a reduced cytokine production and cell-signal transduction. Clinically, we observed that the numbers of CD4(+) or CD8(+)PD-1(low) T cells significantly correlate with a reduced overall survival in FL patients (P=0.007 and 0.04 respectively; n=32). In contrast, the number of CD4(+)PD-1(high) T cells was not associated with patient outcome. Taken together, these results indicated that PD-1 expression defines two sub-populations with distinct functions that differentially impact patient outcome in FL.