NK T cells provide lipid antigen-specific cognate help for B cells.
The mechanisms of T cell help for production of antilipid antibodies are largely unknown. This study shows that invariant NK T cells (iNK T cells) and B cells cooperate in a model of antilipid antigen-specific antibody responses. We use a model haptenated lipid molecule, 4-hydroxy-3-nitrophenyl-alphaGalactosylCeramide (NP-alphaGalCer), to demonstrate that iNK T cells provide cognate help to lipid-antigen-presenting B cells. B cells proliferate and IgG anti-NP is produced from in vivo-immunized mice and in vitro cocultures of B and NK T cells after exposure to NP-alphaGalCer, but not closely related control glycolipids. This B cell response is absent in CD1d(-/-) and Jalpha18(-/-) mice but not CD4(-/-) mice. The antibody response to NP-alphaGalCer is dominated by the IgM, IgG3, and IgG2c isotypes, and marginal zone B cells stimulate better in vitro lipid antigen-driven proliferation than follicular B cells, suggesting an important role for this B cell subset. iNK T cell help for B cells is shown to involve cognate help from CD1d-instructed lipid-specific iNK T cells, with help provided via CD40L, B7-1/B7-2, and IFN-gamma, but not IL-4. This model provides evidence of iNK T cell help for antilipid antibody production, an important aspect of infections, autoimmune diseases, and vaccine development. Our findings also now allow prediction of those microbial antigens that would be expected to elicit cognate iNKT cell help for antibody production, namely those that can stimulate iNKT cells and at the same time have a polar moiety that can be recognized by antibodies.
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, 1 Jimmy Fund Way, Boston, MA 02115, USA.
Elizabeth A
EA
Leadbetter
Manfred
M
Brigl
Petr
P
Illarionov
Nadia
N
Cohen
Megan C
MC
Luteran
Shiv
S
Pillai
Gurdyal S
GS
Besra
Michael B
MB
Brenner
D000818:Animals; D000917:Antibody Formation; D017951:Antigen Presentation; D000938:Antigen-Presenting Cells / Q000276:immunology; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005699:Galactosylceramides / Q000737:chemistry / Q000276:immunology*; D006241:Haptens / Q000737:chemistry / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000276:immunology; D007075:Immunoglobulin M / Q000096:biosynthesis / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D016176:T-Lymphocyte Subsets / Q000276:immunology*
C530070:4-hydroxy-3-nitrophenylgalactosylceramide; D000941:Antigens; D005699:Galactosylceramides; D006241:Haptens; D007074:Immunoglobulin G; D007075:Immunoglobulin M