Molecular Pathway Controlling High-affinity Antibody Production Identified

A molecular pathway has been identified that controls formation of follicular helper T-cells (TFH cells) germinal centers and production of high-affinity antibodies through interaction with the inducible costimulator ICOS via the kinase TBK1 (TANK-binding kinase 1).

Follicular B helper T-cells (also known as just follicular helper T-cells or TFH), are antigen-experienced CD4+ T-cells found in the periphery within B-cell follicles of secondary lymphoid organs such as lymph nodes, spleens, and Peyer's patches, and are identified by their constitutive expression of the B-cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular B- cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate into these seeded germinal centers, predominantly composed of rapidly dividing and mutating B-cells.

Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B-cells that go on to differentiate either into special plasma cells capable of producing high affinity antibodies against foreign antigen, and memory B-cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B-cells in the germinal center. Until now the biomechanisms by which TFH cells mediated germinal center tolerance were not fully understood.

Investigators at the La Jolla Institute for Allergy and Immunology (CA, USA) have unraveled an alphabet soup of molecular connectors that lead to formation of B-cell germinal centers and the production of high-affinity antibodies.

They reported in the May 2, 2016, issue of the journal Nature Immunology that the kinase TBK1 associated with ICOS via a conserved motif, IProx, which shared homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2, and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T-cells severely impaired the differentiation of germinal center TFH cells and the development of germinal centers, interfered with B-cell differentiation, and disrupted the development of antibody responses.

“TFH cells have recently been recognized as important players in the immune system, and we now know they are essential for almost all antibody responses,” said co-senior author Dr. Shane Crotty, professor in the vaccine discovery division at the La Jolla Institute for Allergy and Immunology. “TFH cells control the whole process of generating high affinity antibodies, and ICOS is a receptor molecule strongly required for TFH cells to work. Understand ICOS better, and you can make more TFH when needed, and block it when not needed.”

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La Jolla Institute for Allergy and Immunology