The architecture of neoplastic follicles in follicular lymphoma; analysis of the relationship between the tumor and follicular helper T cells

CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B-cells and have been implicated in the pathogenesis of follicular lymphoma. To further define the role of these cells in follicular lymphoma, we used multiparameter confocal microscopy to compare the architecture of normal and neoplastic follicles and next generation sequencing to analyze the T-cell receptor repertoire in follicular lymphoma lymph nodes. Multiparameter analysis of lymph nodes showed that the proportion of T-follicular helper cells in normal and neoplastic follicles is the same and that the previously reported increase in T-follicular helper cell numbers in follicular lymphoma is thus due to an increase in the number and not content of follicles. As in normal germinal centers, T-follicular helper cells were shown to have a close spatial correlation with proliferating B-cells in neoplastic follicles, where features of immunological synapse formation were observed. The number of T-follicular helper cells in follicular lymphoma correlate with the rate of B-cell proliferation and T-follicular helper cells co-localized to Activation Induced Cytidine Deaminase expressing proliferating B-cells. T-cell receptor repertoire analysis of follicular lymphoma lymph nodes revealed that follicular areas are significantly more clonal when compared to the rest of the lymph node. These novel findings show that neoplastic follicles and germinal centers share important structural features and provide further evidence that T-follicular helper cells may play a role in driving B-cell proliferation and genomic evolution in follicular lymphoma. Our results also suggest that targeting this interaction would be an attractive therapeutic option.