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

Abstract

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.