IL-21 and IL-4 Collaborate To Shape T-Dependent Antibody Responses.
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 (Il21r(-/-)) Ag-specific Tfh cells were used to help immunodeficient Il21r(-/-) B cells following T-dependent immunization. Il21r(-/-) B cells that had received help from WT Tfh cells, but not from Il21r(-/-) 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. Il21r(-/-) 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 Il21r(-/-) 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 Il21r(-/-) 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.
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Helen M
HM
McGuire
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Alexis
A
Vogelzang
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and.
Joanna
J
Warren
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Claudia
C
Loetsch
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and.
Karlo D
KD
Natividad
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Tyani D
TD
Chan
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Robert
R
Brink
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia.
Marcel
M
Batten
Department of Immunology, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia; and St. Vincent's Clinical School, University of New South Wales, Sydney, New South Wales 2052, Australia c.king@garvan.org.au.
Cecile
C
King
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D007073:Immunoglobulin E / Q000097:blood; D053738:Interleukin-21 Receptor alpha Subunit / Q000235:genetics* / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000276:immunology*; D007378:Interleukins / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D011956:Receptors, Cell Surface / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*; D000098546:Interleukin-21; D053662:Interleukin-4 Receptor alpha Subunit
D007073:Immunoglobulin E; D053738:Interleukin-21 Receptor alpha Subunit; D015847:Interleukin-4; D007378:Interleukins; D011956:Receptors, Cell Surface; D000098546:Interleukin-21; C508118:Il21r protein, mouse; C504002:Il4ra protein, mouse; D053662:Interleukin-4 Receptor alpha Subunit