Designing Vaccines: Differentiation and Function of Follicular Helper CD4 T Cells (Tfh Cells)

A video lecture on Tfh cell biology can be seen here.

Germinal centers are the critical sites for the development of long term humoral immunity in the form of antigen-specific memory B lymphocytes and long-lived plasma cells. CD4 T cells are essential for germinal center function. Therefore it is vital to understand the role of CD4 T cell help to B lymphocytes to understand how to better generate long term humoral immunity to pathogens such as viruses and bacteria. (Reviews: Annual Review of Immunology, 2011; Immunity 2014; Nature Reviews Immunology 2015)

The Crotty lab has helped establish that follicular helper CD4 T cells (Tfh) are the uniquely specialized type of CD4 T cell required for germinal centers and most T-dependent humoral immune responses. We
and others established that Bcl6 is a critical transcription factor required for Tfh cell differentiation and function (Science 2009). SAP (Nature 2003, J. Immunology 2010), ICOS (Immunity 2011), B cells (Science 2009, Immunity 2011), IL-6 (PLoS One, 2011; JI Cutting Edge, 2014),
IL-21 (PLoS One 2011), and Itch (Nature Immunology 2014) all have important roles in Tfh cell differentiation. We have shown potent negative regulatory roles for IL-2 (JEM 2012), IL2Ra (CD25) (Immunity 2011, JEM 2012), STAT5 (JEM 2012), Blimp-1 (Science 2009, Immunity 2011, JEM 2012), and the pTEFb complex (Immunity 2014) in Tfh cell differentiation in vivo.

Tfh cells are conserved in humans and are key players in development of humoral immunity (Annual Review of Immunology, 2011; Immunity 2014). Tfh cells can also be major players in autoimmune diseases. Bcl6 is a critical transcription factor regulating Tfh cell differentiation in humans (J. Immunology 2012). Maf is a second transcription factor with important roles in Tfh cell differentiation (J. Immunology 2012). Highly functional memory Tfh cells are associated with potent neutralizing antibody responses in HIV+ individuals (Immunity 2013).

We are focused on understanding Tfh cell differentiation in sufficient detail to be able to manipulate Tfh cell differentiation to maximize Tfh cell responses in new vaccines to maximize the development of protective antibodies and the development of long term humoral immunity.