Follicular lymphoma tumor–infiltrating T-helper (TH) cells have the same polyfunctional potential as normal nodal TH cells despite skewed differentiation

The follicular lymphoma (FL) T-cell microenvironment plays a critical role in the biology of this disease. We therefore determined the lineage, differentiation state, and functional potential of FL-infiltrating CD4(+) T-helper cells (T-H) compared with reactive and normal lymph node (NLN) T-H cells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effector memory T-H cells. We further show differences in the distribution and anatomical localization of CXCR5(+) T-H populations that, on the basis of transcription factor analysis, include both regulatory and follicular helper T cells. On Staphylococcus enterotoxin-B stimulation, which stimulates T cells through the T-cell receptor, requires no processing by APCs, and can overcome regulator T cell-mediated suppression, the proportion of uncommitted primed precursor cells, as well as T(H)2 and T(H)17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of T(H)1 and polyfunctional T-H cells (producing multiple cytokines simultaneously) is similar in FL cells and NLNs. These data suggest that, although T-H-cell differentiation in FL is skewed compared with NLNs, FL T-H cells should have the same intrinsic ability to elicit antitumor effector responses as NLN T-H cells when tumor suppressive mechanisms are attenuated. (Blood. 2011;118(13):3591-3602)