Intratumoral CD4⁺CD25⁺ regulatory T-cell-mediated suppression of infiltrating CD4⁺ T cells in B-cell non-Hodgkin lymphoma

Most non-Hodgkin lymphomas (NHLs) are of B-cell origin, but the tumor tissue can be variably infiltrated with T cells. In the present study, we have identified a subset of CD4⁺CD25⁺ T cells with high levels of CTLA-4 and Foxp3 (intratumoral T_reg cells) that are overrepresented in biopsy specimens of B-cell NHL (median of 17% in lymphoma biopsies, 12% in inflammatory tonsil, and 6% in tumor-free lymph nodes; P = .001). We found that these CD4⁺CD25⁺ T cells suppressed the proliferation and cytokine (IFN-γ and IL-4) production of infiltrating CD4⁺CD25^- T cells in response to PHA stimulation. PD-1 was found to be constitutively and exclusively expressed on a subset of infiltrating CD4⁺CD25^- T cells, and B7-H1 could be induced on intratumoral CD4⁺CD25⁺ T cells in B-cell NHL. Anti-B7-H1 antibody or PD-1 fusion protein partly restored the proliferation of infiltrating CD4⁺CD25^- T cells when cocultured with intratumoral T_reg cells. Finally, we found that CCL22 secreted by lymphoma B cells is involved in the chemotaxis and migration of intratumoral T_reg cells that express CCR4, but not CCR8. Taken together, our results suggest that T_reg cells are highly represented in the area of B-cell NHL and that malignant B cells are involved in the recruitment of these cells into the area of lymphoma.