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 (FL). To further define the role of these cells in FL, 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 FL lymph nodes (LN). Multiparameter analysis of LN showed that the proportion of T-foilicular helper cells (T-FH) in normal and neoplastic follicles is the same and that the previously reported increase in T-FH numbers in FL is thus due to an increase in the number and not content of follicles. As in normal germinal centers, T-FH were shown to have a dose spatial correlation with proliferating B cells in neoplastic follicles, where features of immunological synapse formation were observed. The number of T-FH in FL correlate with the rate of B-cell proliferation and T-FH co-localized to activation induced cytidine deaminase expressing proliferating B cells. T-cell receptor repertoire analysis of FL LN revealed that follicular areas are significantly more clonal when compared to the rest of the LN. These novel findings show that neoplastic follicles and germinal centers share important structural features and provide further evidence that T-FH may play a role in driving B-cell proliferation and genomic evolution in T-FH. Our results also suggest that targeting this interaction would be an attractive therapeutic option.