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

Immunol Rev. 2020 Jul;296(1):48-61. doi: 10.1111/imr.12860. Epub 2020 May 15.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism*
  • Biomarkers, Tumor
  • Cell Differentiation
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / immunology
  • Cell Transformation, Neoplastic / metabolism
  • Clonal Selection, Antigen-Mediated
  • Disease Management
  • Disease Susceptibility
  • Genetic Predisposition to Disease
  • Germinal Center / immunology*
  • Germinal Center / metabolism*
  • Humans
  • Lymphoma / diagnosis
  • Lymphoma / etiology*
  • Lymphoma / metabolism*
  • Lymphoma / therapy
  • Mutation
  • T Follicular Helper Cells / immunology*
  • T Follicular Helper Cells / metabolism*


  • Biomarkers, Tumor