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Interleukin-21 and interleukin-4 collaborate to shape T dependent antibody responses

Abstract

The selection of affinity-matured Ab-producing B cells is supported by interactions with T follicular helper (Tfh) cells. In addition to cell surface?expressed molecules, cytokines produced by Tfh cells, such as IL-21 and IL-4, provide B cell helper signals. In this study, we analyze how the fitness of Th cells can influence Ab responses. To do this, we used a model in which IL-21R?sufficient (wild-type [WT]) and ?deficient (Il21r2/2) Ag-specific Tfh cells were used to help immunodeficient Il21r2/2 B cells following T- dependent immunization. Il21r2/2 B cells that had received help from WT Tfh cells, but not from Il21r2/2 Tfh cells, generated affinity-matured Ab upon recall immunization. This effect was dependent on IL-4 produced in the primary response and associated with an increased fraction of memory B cells. Il21r2/2 Tfh cells were distinguished from WT Tfh cells by a decreased frequency, reduced conjugate formation with B cells, increased expression of programmed cell death 1, and reduced production of IL-4. IL-21 also influenced responsiveness to IL-4 because expression of both membrane IL-4R and the IL-4?neutralizing soluble (s)IL-4R were reduced in Il21r2/2 mice. Furthermore, the concentration of sIL-4R was found to correlate inversely with the amount of IgE in sera, such that the highest IgE levels were observed in Il21r2/2 mice with the least sIL-4R. Taken together, these findings underscore the important collaboration between IL-4 and IL-21 in shaping T-dependent Ab responses. The Journal of Immunology, 2015, 195: 000?000.

Type Journal
Authors McGuire, HM; Vogelzang, A; Warren, J; Loetsch, C; Natividad, KD; Chan, TD; Brink, R; Marcel, B; King, C.
Garvan Authors Helen Lenthall
Publisher Name J IMMUNOL
Published Date 2015-12-01 00:00:00
Published Volume 10
Published Issue 4049
Published Pages 5123-25
Status Published in-print