Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner


Mouse invariant natural killer T cells (iNKT cells) provide cognate and noncognate help for lipid and protein-specific B cells, respectively. However, the long-term outcome for B cells after cognate help is provided by iNKT cells is unknown at present. Here we found that cognate iNKT cell help resulted in a B cell differentiation program characterized by extrafollicular plasmablasts, germinal-center formation, affinity maturation and a robust primary immunoglobulin G (IgG) antibody response that was uniquely dependent on iNKT cell–derived interleukin 21 (IL-21). However, cognate help from iNKT cells did not generate an enhanced humoral memory response. Thus, cognate iNKT cell help for lipid-specific B cells induces a unique signature that is a hybrid of classic T cell–dependent and T cell–independent type 2 B cell responses.

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Figure 1: Stimulation of B cells with cognate antigen (lipid) or noncognate antigen (lipid plus protein) induces splenic extrafollicular foci.
Figure 2: Stimulation of B cells with cognate antigen (lipid) or noncognate antigen (lipid plus protein) leads to the development of splenic GCs.
Figure 3: Cognate and noncognate iNKT cell help induces antigen-specific antibody affinity maturation.
Figure 4: IL-21R signaling is required for cognate iNKT cell–mediated anti-NP responses.
Figure 5: IL-21 produced by iNKT cells is required for cognate lipid antigen help.
Figure 6: Only noncognate iNKT cell help induces antibody memory response after day 177 rechallenge.
Figure 7: Only noncognate iNKT cell help induces an antibody memory response after rechallenge on day 46.


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We thank M. Nussenzweig (Rockefeller University) for B6.SJL B1-8hi mice; M. Exley (Dana Farber Cancer Institute) for C57BL/6 Vα14-transgenic mice and C57BL/6 Jα18-deficient mice; K. Rajewsky (Center for Blood Research) for B1-8f mice; M. Rincon (University of Vermont) for IL-21-deficient mice; and the US National Institutes of Health Tetramer Core for mouse CD1d-PBS57 tetramers and unloaded CD1d tetramers. Supported by the Trudeau Institute (E.A.L.), the US National Institutes of Health (AI028973-23 and AI063428-06 to M.B.B. and T32 A1049823-10 to I.L.K.), J. Bardrick (G.S.B.), the Royal Society (G.S.B.), The Wellcome Trust (084923/B/08/Z to G.S.B.) and the Medical Research Council (G.S.B.).

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I.L.K. designed and did experiments, analyzed data and edited the manuscript; A.F., M.T., J.D. and G.F.M.W. designed and did experiments; A.M.H. did experiments, edited the manuscript and provided technical advice; N.V. and G.S.B. synthesized and provided lipid antigens; M.M. and M.B.B. provided conceptual advice and E.A.L. initiated and directed the research, did experiments, analyzed the data and wrote the manuscript.

Corresponding author

Correspondence to Elizabeth A Leadbetter.

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The authors declare no competing financial interests.

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King, I., Fortier, A., Tighe, M. et al. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat Immunol 13, 44–50 (2012).

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