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

Xun Wu; J Ernesto Fajardo-Despaigne; Christine Zhang; Vishala Neppalli; Versha Banerji; James B Johnston; Spencer B Gibson; Aaron J Marshall

doi:10.3389/fonc.2021.674492

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

Front Oncol. 2021 Apr 28:11:674492. doi: 10.3389/fonc.2021.674492. eCollection 2021.

Authors

Xun Wu¹, J Ernesto Fajardo-Despaigne¹, Christine Zhang¹, Vishala Neppalli², Versha Banerji^{3

4}, James B Johnston^{3

4}, Spencer B Gibson^{1

3

4}, Aaron J Marshall^{1

3

4

5}

Affiliations

¹ Department of Immunology, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
² Hematopathology Laboratory, Shared Health Manitoba, Winnipeg, MB, Canada.
³ Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada.
⁴ Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
⁵ Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Abstract

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.

Keywords: T follicular helper (Tfh) cell; TIGIT; bone marrow; chronic lymphocytic leukemia (CLL); coculture assay; ibrutinib; interleukin 21 (IL-21).