T follicular helper cells in germinal center B cell selection and lymphomagenesis

Abstract

Germinal centers (GCs) are confined anatomic regions where rapidly proliferating B cells undergo somatic mutation and selection and eventual differentiation into memory B cells or long-lived plasma cells. GCs are also the origin of malignancy, namely follicular lymphoma (FL), GC B cell-diffuse large B cell lymphoma (GCB-DLBCL), and Burkitt lymphoma (BL). GC B cell lymphomas maintain their GC transcriptional signatures and sustain many features of the GC microenvironment, including CD4⁺ T follicular helper (Tfh) cells. Tfh cells are essential for the formation and maintenance of GCs, providing critical helper signals such as CD40L. Large-scale sequencing efforts have led to new insights about the tightly regulated selection mechanisms that are commonly targeted during GC B cell lymphomagenesis. For instance, HVEM, a frequently mutated surface molecule in GC-derived lymphomas, engages the inhibitory receptor BTLA on Tfh cells and loss of HVEM leads to exaggerated T cell help. Here, we review current understanding of how Tfh cells contribute to the selection of GC B cells, with a particular emphasis on how Tfh cell signals may contribute to lymphomagenesis. The possibility of targeting Tfh cells for the treatment of GC-derived lymphomas is discussed.

Keywords: BTLA; Germinal center B cell; HVEM; PD-1; PD-L1; T follicular helper cell; immunotherapy; lymphoma.

Figure 1.. Common mutations in germinal center (GC)-derived lymphomas

Venn diagram of mutations found in follicular lymphoma (FL) and germinal center diffuse large B cell lymphoma (GC-DLBCL) ^,,. Common mutations shared by FL and GC-DLBCL include BCL2, CREBBP, EZH2, GNA13, TNFRSF14, SOCS1, and STAT6.

Figure 2.. Follicular lymphoma (FL) germinal center B cells receive exaggerated helper cues from T follicular helper (Tfh) cells

(A) Germinal center microenvironment in a LN with a follicular lymphoma tumor. The follicular lymphoma GC contains stromal follicular dendritic cells (FDC, purple), GC B cells (blue), and Tfh cells (yellow). (B) Magnification of GC light zone where a Bcl2 translocated GC B cell is presenting antigen to a Tfh cell and is transmitting and receiving normal positive selection (left of TCR-MHCII) and negative selection (right of TCR-MHCII) signals. (C) Magnification of a FL GC B cell’s interaction with a Tfh cell in which several of the key molecular regulators are altered by AID-induced mutations, as detailed in the text. In this example, there is increased IL-4 production, increased CD40L due to the absence of BTLA-HVEM, and mutations in Fas death domain that prevents FasL-mediated cell death. Small box in B and C shows relative strength of helper signal from Tfh cell to B cell.

Figure 3.. Model of BTLA action as a cell-extrinsic suppressor of GC lymphomagenesis

(A) HVEM-expressing GC B cell recruits BTLA to immunological synapse. BTLA signals into Tfh cell through SHP-1, which reduces the strength of TCR signal and amount of preformed CD40L mobilized to the cell surface. (B) In the absence of HVEM, BTLA is not recruited to the immune synapse and the amount of preformed CD40L mobilized to the surface is increased. The HVEM-deficient B cell receives increased CD40 signaling.