Functional role of follicular helper T cells in chronic lymphocytic leukemia
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Date
2020-08-19
Authors
Fajardo Despaigne, Joaquin Ernesto
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Abstract
Chronic lymphocytic leukemia (CLL) is the most common blood malignancy in Western countries. CLL patients have elevated numbers of malignant B cells (CLL-B) in the blood and lymphoid tissues. In the lymph nodes, CLL-B cells form pseudofollicles where they interact with other cell types, including CD40 ligand (CD40L)-expressing helper T cells, receiving stimulatory signals that are critical for disease progression. Our lab became interested in T follicular helper (Tfh) cells because these cells can migrate to the B cell zone in normal germinal center reactions. Tfh cells also express molecules that could potentially promote CLL-B cell survival, activation and proliferation. Our lab recently reported that CLL patients present an elevated frequency and activation of circulating Tfh cells and these results correlated with disease stage. CLL Tfh cells were also skewed towards a T helper 1 (Th1)-like subset (Tfh1), with decreased levels of Tfh2. The present study shows that, compared to CLL non-Tfh and control Tfh, CLL Tfh cells have increased expression of the CLL-supportive molecules CD40L, IL-21, TIGIT and PD-1. Within Tfh cells, the Tfh1 subset had the highest frequency of cells expressing these molecules and also IFN-γ. Cells expressing Tfh and Th1 markers were observed within CLL lymph node pseudofollicles of one patient. Other alterations in the helper T cell compartment in CLL were found, including higher frequency and altered phenotype of regulatory T cells and trends to an increase in effector memory cells and decrease in naïve and central memory populations. A co-culture system of autologous CD4 T:CLL-B cells was used to assessed the functional role of CD4 T and Tfh cells in CLL-B cell support. Activated CD4 T cells promoted CLL cell activation, survival and proliferation. The frequency of Tfh cells was associated with B cell proliferation in the system. The culture of un-activated CD4 T cells with CLL-B cells promoted preferential upregulation of CD69 on Tfh, compared to non-Tfh cells. The results of this study suggest that Tfh cells play a tumor-supportive function in CLL and that targeting the Tfh:CLL interaction could have clinical value.
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Keywords
Chronic lymphocytic leukemia, Follicular helper T cells, Cancer, B cells, Flow cytometry