Dissecting the role of HVEM and BTLA in constraining the germinal center B cell response

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Project summary/abstract Germinal centers (GC) are regions in lymphoid organs where activated B cells are selected for their ability to bind antigen with high affinity as well as generate memory B cells and high affinity antibodies. GC B cells have the unique ability to improve their affinity to the immunizing antigen during an immune response through a process of somatic hypermutation and selection. Although somatic hypermutation targets the immunoglobulin genes, off-target mutations also occur and contribute to the malignant transformation of GC B cells into a subset of non-Hodgkin B cell lymphomas. Our understanding of GC B cell biology has been greatly enriched by understanding how such mutations over-ride the normal constraints to GC B cell growth. For instance, our lab has shown S1PR2’s role in confining GC B cells to the GC and inhibiting growth by antagonizing Akt signaling. HVEM, a TNF receptor superfamily member (also called TNFRSF14), is frequently mutated in germinal center (GC) derived non-Hodgkin B cell lymphomas such as follicular lymphoma and diffuse large B cell lymphoma. The mutations found in HVEM are predicted to lead to loss of the protein’s function, suggesting an important growth regulatory role for HVEM in GC B cells. However, HVEM’s function in B cells has not been directly examined. HVEM is highly expressed on follicular B cells and is expressed at a lower level on GC B cells, possibly suggesting an advantage to more finely tuned signaling in the GC. In preliminary studies we have found that deficiency in HVEM results in a cell intrinsic expansion of GC B cells. Of HVEM’s binding partners, the immunoglobulin (Ig) superfamily co-inhibitory receptor B and T lymphocyte attenuator (BTLA) is most highly expressed in the GC. BTLA is highly expressed on T follicular helper (Tfh) cells and BTLA deficiency in antigen- specific CD4+ T cells increases IL-21 production and GC B cell expansion, suggesting a regulatory role of BTLA on Tfh cells. Tfh cells have a crucial role in GC B cell selection and several molecular regulators have been shown to tune the degree of T cell help provided to the GC B cell. We hypothesize that HVEM acts as a suppressor of GC B cell responses through its interaction with BTLA, a potential negative regulator of B and T cell engagement. Specifically, we aim to assess how HVEM regulates the magnitude of the GC B cell response and if it impacts the induction of long-lived humoral immunity (1); and to examine if BTLA expression on T follicular helper cells moderates the amount of T cell help during the GC reaction (2). This work will define a novel negative regulator of the GC B cell response, which can lead to a rational target for vaccine development, immunotherapy, and treatment for GC-derived B cell lymphomas.