Phenotype of neoplastic cells in angioimmunoblastic T-cell lymphoma is consistent with activated follicular B helper T cells

We read the letter by Grogg et al,¹  recently published in Blood, with great interest. The authors demonstrated that CD10⁺ T cells in angioimmunoblastic T-cell lymphoma²  (AITL) coexpress CXCL13 and proposed that AITL is a neoplasm of germinal center (GC) T-helper cells.

We have hypothesized that neoplastic T cells may be related to follicular B helper T (T_FH) cells,^3-6  since CD10⁺ atypical T cells were found to be in intimate contact with the expanded meshwork of proliferating follicular dendritic cells (FDCs), a characteristic of AITL. Therefore, we have performed consecutive double immuno-labeling to analyze expression of some known T_FH cell functional antigens (CXCR5, CD154/CD40L, CD134/OX40, and CD57) in the CD10⁺ T cells in 20 paraffin-embedded AITL cases. Since Kim et al⁷  and Chtanova et al⁸  established that CXCL13 is highly up-regulated in T_FH cells, expression of this antigen was also investigated; the same has also been done by Grogg et al.¹ 

In 18 of 20 cases, the expression of CD10 on 5% to 30% of T cells strongly correlated with CXCL13 production. The remaining 2 cases exhibited CXCL13⁺ atypical T cells without apparent CD10 expression. The neoplastic T cells, as defined by CD10 as well as CXCL13 expression, revealed a CXCR5⁺CD134⁺CD154⁺ CD57^–/+ immunophenotype (Figure 1), which is most consistent with GC outer-zone T_FH cells.⁶  All cases displayed concomitant expression of CXCL13 and CXCR5 in neoplastic T cells, again pointing to a T_FH phenotype.^3-8  Coexpression of the CXCR5 chemokine receptor and its ligand CXCL13 suggests an autocrine loop, possibly contributing to the survival of neoplastic T cells. All cases demonstrated coexpression of CD154 in the majority of the neoplastic T cells. This antigen plays a crucial role in GC formation⁹  and provides survival signals to follicular B cells.⁶  Each case showed significant but variable numbers (10%-100%) of CXCL13⁺ T cells bearing CD134, whose expression on activated CD4⁺ T cells either initiates their migration into or causes them to be retained in B follicles.¹⁰  One case coexpressed CD57 in a significant proportion of neoplastic cells, while the remaining cases displayed only a minute fraction of CD57⁺CXCL13⁺ cells that may reflect the residual normal T_FH cells. Since proliferating FDCs expressed CXCL13 and are known to express CD40⁹  (receptor for CD154) and OX40L^6,10  (ligand for CD134), our data suggest a selective cross-talk between FDCs and neoplastic T cells.

Our observations not only fully support the notion of Grogg et al¹  but extend it by a more detailed analysis, establishing that the phenotype of the neoplastic cells (as shown here) is consistent with activated T_FH cells localized at the boundary between the mantle zone and the GC light zone.⁶  These findings provide direct explanations for some peculiar features of AITL, including B-cell hyperactivation and hypergammaglobulinemia despite gradual reduction of follicular B-cell mass, as well as the follicular outgrowths of FDCs as a result of stimulation by neoplastic T_FH cells. Further investigations will be needed to explain loss of follicular B cells, a phenomenon that occurs in advanced cases and may be caused by a disarranged dialogue between neoplastic T_FH cells and nonneoplastic B cells.