Altered T Follicular Helper Cell Subsets and Function in Chronic Lymphocytic Leukemia

Follicular helper T cells (T_FH) have specialized properties in promoting normal B cell activation but their role in chronic lymphocytic leukemia (CLL) is unknown. We find that T_FH cells are elevated in CLL patients and are phenotypically abnormal, expressing higher levels of PD-1, TIGIT, CD40L, IFNγ and IL-21, and exhibiting abnormal composition of T_FH1, T_FH2 and T_FH17 subsets. Frequencies of CD4-positive T cells expressing T_FH1 markers and IL-21 were positively correlated with patient lymphocyte counts and RAI stage, suggesting that accumulation of abnormal T_FH cells is concomitant with expansion of the leukemic B cell clone. Treatment with ibrutinib led to normalization of T_FH frequencies and phenotype. T_FH cells identified in CLL bone marrow display elevated expression of several functional markers compared to blood T_FH cells. CLL T cell-B cell co-culture experiments revealed a correlation of patient T_FH frequencies with functional ability of their CD4-positive T cells to promote CLL proliferation. Conversely, CLL cells can preferentially activate the T_FH cell subset in co-culture. Together our results indicate that CLL development is associated with expansion of abnormal T_FH populations that produce elevated levels of cytokines and costimulatory molecules which may help support CLL proliferation.