Advances in understanding of angioimmunoblastic T-cell lymphoma

Abstract

It has been nearly half a century since angioimmunoblastic T-cell lymphoma (AITL) was characterized in the early 1970's. Our understanding of the disease has dramatically changed due to multiple discoveries and insights. One of the key features of AITL is aberrant immune activity. Although AITL is now understood to be a neoplastic disease, pathologists appreciated that it was an inflammatory condition. The more we understand AITL at cellular and genetic levels, the more we view it as both a neoplastic and an inflammatory disease. Here, we review recent progress in our understanding of AITL, focusing on as yet unsolved questions.

Fig. 1. Relative frequencies of non-cutaneous PTCLs.

IPTCLP International PTCL Project, ALK anaplastic lymphoma kinase, ALCL anaplastic large cell lymphoma, EATL enteropathy-associated T-cell lymphoma. *1, calculated as 87.8% (frequency of PTCL and ENKTL after excluding non-PTCL cases in IPTCLP) of 450 (number of cases registered in Europe in IPTCLP). *2, calculated excluding ATLL from *1. a Frequencies including ATLL. b Frequencies excluding ATLL.

Fig. 2. Physiologic and non-physiologic germinal center reactions.

(a) Germinal center reaction in physiologic condition. Both Tfh-primed cells and B cells together form the GC, where GC B cells begin proliferating at the dark zone and undergo somatic hypermutation. In the light zone, FDCs participate in the network and contribute to selection of affinity-matured GC B cells. In the light zone, GC B cells make one of the three choices: re-entry to the dark zone, differentiation into plasmablast/plasma cells, or differentiation into memory B cells. For all of these processes, CD40 ligand (CD40L) expressed on the Tfh cell membrane and interleukin-21 (IL-21), IL-4, and CXCL13 secreted by Tfh cells play important roles in GC B-cell activation. Engagements of MHC class II, CD40, and ICOS ligand on GC B cells with the TCR, CD40L, and ICOS on Tfh cells, respectively, are of particular importance in terms of direct cell-to-cell contact. Also see the text for additional explanations. (b) Germinal center reaction in the presence of Tet2 disruption in B cells shown in mice. Follicular hyperplasia is caused by impaired exit of GC B cells from the GC light zone. Tfh follicular helper T cell, GCB germinal center B cell, activated B activated B cell, Tfh-primed CD4⁺ Tfh-primed CD4⁺ T cell, naive CD4⁺ naive CD4⁺ T cell, memory B memory B cell, mDC myeloid dendritic cell, FDC follicular dendritic cell, HSC hematopoietic stem cell, Th1 T helper 1 cell, eosino eosinophil. ICOSL ICOS ligand, MHC/Ag antigen presented on major histocompatibility complex, TCR T-cell receptor, CD40L CD40 ligand, BCR B-cell receptor, VEGF vascular endothelial growth factor. GC germinal center, LZ light zone, DZ dark zone, BM bone marrow, LN lymph nodes. SHM somatic hypermutation, mut mutation. Red closed circles indicate antigen localized on FDC.

Fig. 3. Schematic model of AITL generation.

In the bone marrow (BM), somatic mutations in TET2 (or TET2 plus DNMT3A; marked as TET2 and DNMT3A) result in clonal hematopoiesis. TET2 alone or TET2 plus DNMT3A mutated hematopoietic stem cells (HSC) can give rise to thymocytes. TET2 plus DNMT3A mutated HSC generate more CD4⁺ T cells than CD8⁺ T cells. TET2^* indicates TET2 mutation alone or TET2 plus DNMT3A mutations. TET2 alone or TET2 plus DNMT3A mutated naive CD4⁺ T cells are primed to Tfh cells by the contact with myeloid DC cells, and migrate to the T-B border. The TET2 mutation (or TET2 plus DNMT3A mutations)-carrying Tfh-primed cells contact with the TET2-mutated activated B cells, then acquire the RHOA^G17V mutation (RHOA) before or after differentiation into Tfh cells (Tfh). These Tfh cells should further interact with B cells (“B”) derived from activated B cells at the follicle-destroyed lymph nodes. The Tfh cells carrying TET2 (or TET2 plus DNMT3A) plus RHOA mutations may further acquire the IDH2 mutation (IDH2). RHOA mutation alone or RHOA plus IDH2 mutations are designated as RHOA^*. Ultimately, mutations in TCR-related genes (TCRr) are acquired. TET2-mutated B cells are infected with EBV and/or acquire mutations in genes such as NOTCH1. These Tfh cells and B cells with individually accumulated mutations still contact and activate each other through ICOS-L and ICOS ligation and still unknown mechanisms (designated as “?”). Some of the B cells take a morphology as immunoblasts or HRS cells, and B-cell lymphoma arises. See the text for the further scenario. LN lymph nodes, Thy thymus. HSC hematopoietic stem cell, naive CD4⁺ naive CD4⁺ T cell, Tfh-primed Tfh-primed CD4⁺ T cell, Tfh follicular helper T cell, activated B activated B cell, Th17 T helper 17 cell, Th1 T helper 1 cell, Th2 T helper 2 cell, eosino eosinophil, plasma plasma cell, FDC follicular dendritic cell, HEV high endothelial venule. ICOSL ICOS ligand, MHC/Ag antigen presented on major histocompatibility complex, TCR T-cell receptor, BCR B-cell receptor, VEGF vascular endothelial growth factor.