T follicular helper cell (TFH) differentiation and context-dependent TFH heterogeneity regulate B cell CSR and isotypes. Following activation of naïve CD4+ T cells, TH cells proliferate and undergo fate decisions in response to cytokines and other differentiating factors. TFH and B cell differentiation and isotypes are influenced by IL-6 and IL-21, and dependent on CD40 and ICOS signaling for expression of the transcription factor Bcl6. Cytokines including IL-12, IL-4, IL-1β, and many others, direct (A) TH1 and IgG; (B) TH2, IgG and IgE, (C) TH17, mucosal IgM and IgA and (D) regulatory cell differentiation. The microenvironment-dependent cytokines influence TFH and B cell differentiation, lineages, and isotypes, which define their fate to be pro- or anti-tumorigenic.