Long-lived pathogen-specific antibodies develop primarily as a result of germinal center (GC) reactions, wherein specialized interactions between GC B cells and follicular helper T cells (Tfh) promote B cell activation, somatic hypermutation and immunoglobulin class switching. The goal of many vaccines is to generate sustained levels of high affinity antibodies capable of neutralizing pathogens, an outcome that is dependent upon the induction of a robust GC response. Unfortunately, efficacious vaccines have been difficult to produce for several major human pathogens, including HIV, presumably because vaccine-induced GC responses were not strong enough to promote the extensive affinity maturation required to produce broadly neutralizing antibodies. Better characterization of regulatory mechanisms governing the quality of GC responses should provide targets for interventions that would enhance new vaccine regimens to stimulate protective humoral immune responses. Natural killer (NK) cells are an innate lymphocyte that we previously demonstrated to play a vital role in suppressing antiviral T cell responses during persistent virus infection. We now find that NK cells also suppress GC responses by restricting the number of GC B and Tfh cells. NK cell- mediated inhibition of the GC response was associated with fewer long-lived virus-specific plasma cells and an impaired development of neutralizing antibodies following acute infection. Furthermore, a subset of NK cells displayed increased expression of the B cell follicle-homing receptor, CXCR5, after infection. Thus, up- regulation of CXCR5 represents a potential mechanism whereby NK cells can localize to germinal centers and suppress GC expansion. We will determine whether CXCR5 expression by NK cells defines a subset of regulatory NK cells that localize to B cell follicles to suppress GC responses during infection and immunization. Moreover, we will evaluate the contribution of the transcription factor, NFAT2, in controlling the expression of CXCR5 and other genes associated with the regulation of humoral immunity by NK cells, thereby endowing this subset of NK cells with unique immunosuppressive properties. An improved understanding of the mechanism determining NK cell-mediated suppression of humoral immunity will provide new targets of therapeutic interventions during immunization with the goal of improving GC responses and the development of protective antibodies.
Effective vaccines stimulate long-lasting protective antibodies, but not all vaccine attempts against important human pathogens have been effective at eliciting these types of antibodies. Therefore, identifying new mechanisms governing generation of protective antibodies will provide insight into pathways that can be targeted to improve such responses during vaccination. We have discovered a previously unappreciated role for natural killer cells in the suppression of antibody responses. In the proposed work we will elucidate the characteristics of these potent inhibitory cells so that innovative strategies t prevent this immune impairment can be developed in order to enhance the efficacy of next-generation vaccine regimens.
| Rydyznski, Carolyn E; Cranert, Stacey A; Zhou, Julian Q et al. (2018) Affinity Maturation Is Impaired by Natural Killer Cell Suppression of Germinal Centers. Cell Rep 24:3367-3373.e4 |
| Waggoner, Stephen N; Reighard, Seth D; Gyurova, Ivayla E et al. (2016) Roles of natural killer cells in antiviral immunity. Curr Opin Virol 16:15-23 |
| Rydyznski, Carolyn E; Waggoner, Stephen N (2015) Boosting vaccine efficacy the natural (killer) way. Trends Immunol 36:536-46 |
