Angioimmunoblastic T-cell lymphoma: a neoplasm of germinal-center T-helper cells?

We have read the paper by Kim et al¹  recently published in Blood with great interest. The study reports the gene-expression profile of germinal-center T-helper (GC-Th) cells and identifies genes differentially expressed by G-C-Th cells compared with other T-cell subsets.

The germinal center microenvironment not only is an essential niche for generation of B-cell response, but also is considered to be critical in the development of most human lymphoid neoplasms. Although most lymphomas originating from germinal-center lymphocytes are B-cell lymphomas, it has been suggested recently that some peripheral T-cell lymphomas,²  in particular angioimmunoblastic T-cell lymphoma (AITL), may arise from GC-Th cells.^3,4  AITL is a relatively infrequent disease accounting for 1% to 2% of all lymphomas. Typically, the tumor cells of AITL have a T-helper-cell phenotype expressing CD3, CD4, and frequently CD10, similar to a subset of normal GC-Th cells.⁴  In early lymph-node involvement by AITL, the neoplastic T cells preferentially occupy the B-cell follicles and immediate perifollicular area, sometimes mimicking a follicular lymphoma of B-cell origin.^2,3,5  This suggests that the follicle-center microenvironment is critical for tumor development.

In the Kim et al¹  study, one of the most highly up-regulated genes in the GC-Th cell subset was CXCL13, a chemokine critical for B-cell entry into germinal centers.⁶  Based on this observation, we investigated the expression of CXCL13 in AITL. We stained paraffin sections of 29 AITL lymph-node biopsies using a monoclonal antibody against CXCL13 (Clone 53610; R&D Systems, Minneapolis, MN) and standard immunohistochemical methods. All cases were previously characterized by immunohistochemical studies that documented expression of CD3 and CD4 by the tumor cells. CD10 was expressed in 22 cases. We observed striking cytoplasmic expression of CXCL13 by the vast majority of the tumor cells (> 80%) in 25 (86%) of 29 AITL cases studied. The tumor cells both within the follicles and in the interfollicular areas stained with similar intensity. All 22 cases expressing CD10 also expressed CXCL13 (Figure 1). In addition, a subset of the macrophages and follicular dendritic cells (FDCs) was labeled by CXCL13.

The expression of CXCL13 by AITL provides another piece of evidence linking the tumor cells to GC-Th cells. Increased CXCL13 message in AITL was also detected by transcription-profiling studies using cDNA chips designed to detect chemokine-gene expression.⁷  Kim et al¹  also reported selective up-regulation of several transcription factors in GC-Th cells. One of these was Bcl-6, which, like CXCL13, is overexpressed in AITL.⁸ 

These observations are important in several respects. One of the downstream effects of CXCL13 expression is induction and proliferation of FDCs, probably via stimulation of lymphotoxin-alpha production by B cells.⁶  Of interest, the proliferation of FDCs is a morphologic hallmark of AITL and is considered to be a requirement for histologic diagnosis.⁹  Another attribute of AITL is the presence of dysregulated B-cell growth. In early stages, this is primarily seen as follicular hyperplasia^3,5 ; in later stages, a more immunoblastic and plasmacytic expansion with hypergammaglobulinaemia occurs.^3,10  As CXCL13 is a critical factor in B-cell recruitment and activation, it may also be responsible for some of the B-cell abnormalities seen in AITL. Marked immune dysregulation, rather than aggressive tumor growth, is thought to be the main clinical problem in AITL, and there are attempts to treat this disease using immunomodulatory approaches.^11,12  The information gained by studying normal follicle-center T cells may be helpful in the development of targeted immunomodulatory treatment strategies for this otherwise-fatal condition. The study by Kim et al¹  elegantly demonstrates how such critical biologic information on tumors can be acquired by examining the putative cell of origin.