Fyn Kinase Is Required for Optimal Humoral Responses

Natalia S Chaimowitz,John J Ryan,Daniel H Conrad,Yves T Falanga

doi:10.1371/journal.pone.0060640

Abstract

The generation of antigen-specific antibodies and the development of immunological memory require collaboration between B and T cells. T cell-secreted IL-4 is important for B cell survival, isotype switch to IgG1 and IgE, affinity maturation, and the development of germinal centers (GC). Fyn, a member of the Src family tyrosine kinase, is widely expressed in many cell types, including lymphocytes. This kinase is known to interact with both the B cell and T cell receptor (BCR and TCR, respectively). While Fyn deletion does not impair the development of immature T cells and B cells, TCR signaling is altered in mature T cells. The current study demonstrates that Fyn deficient (KO) B cells have impaired IL-4 signaling. Fyn KO mice displayed low basal levels of IgG1, IgE and IgG2c, and delayed antigen-specific IgG1 and IgG2b production, with a dramatic decrease in antigen-specific IgG2c following immunization with a T-dependent antigen. Defects in antibody production correlated with significantly reduced numbers of GC B cells, follicular T helper cells (TFH), and splenic plasma cells (PC). Taken together, our data demonstrate that Fyn kinase is required for optimal humoral responses.

Highlights

The development of immunological memory is critical for longterm protection against pathogen infection
Our results demonstrate that Fyn KO B cells have decreased antibody production following in vitro activation, coincident with impaired STAT3 and STAT5 phosphorylation upon IL-4Ra stimulation
Our results demonstrate that 14 days post-immunization, Fyn KO mice displayed significantly decreased levels of germinal centers (GC) B cells compared to wild type (WT) controls (Figures 4a, 4b)

Summary

Introduction

The development of immunological memory is critical for longterm protection against pathogen infection. Within GCs, B cells undergo class switch recombination (CSR) and somatic hypermutation (SHM), leading to the development of PCs that secrete high affinity, class switched antibodies. During B cell-T cell interaction, TFH provide B cell help via CD40L and cytokines, such as IL-21 and IL-4. Both of these cytokines are important for germinal center formation. Even prior to the discovery of TFH cells, it was demonstrated that optimal GCs did not form in IL-4Ra or IL-4 KO mice, suggesting the importance of this cytokine pathway. In addition to being required for GC formation, IL-4 signaling pathway is critical for immunoglobulin class switch recombination and somatic hypermutation [1,2,3]

Methods

Results

Conclusion