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 Hcells. Relative to NLNs, FL cells have decreased proportions of naive and central memory but increased proportions of effectormemory 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 H2 and T H17 cells is higher in FL cells than in reactive lymph nodes or NLNs. However, the proportion of T H1 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 Hcells when tumor suppressive mechanisms are attenuated. © 2011 by The American Society of Hematology.