Differential MyD88/IRAK4 requirements for cross-priming and tumor rejection induced by heat shock protein 70-model antigen fusion protein.
Priming of CD8(+) T cells requires two signals, one produced by T-cell receptor recognition of antigen, and a second that is often provided by the innate immune response. In this context, antigens non-covalently or covalently associated with heat shock proteins (HSP) are internalized and processed in antigen-presenting cells (APC) to be presented by MHC I molecules to CD8(+) T cells, thus, signal 1 has been well characterized in this pathway of cross-presentation. Signal 2 is not fully understood, although there are reports that Toll-like receptors (TLRs) interact with HSP and activate APC. The ability of HSP to activate APC through TLRs is, however, controversial because of the possibility of endotoxin contamination. Using a variety of TLR KO mice, we present evidence that TLRs (TLR2, 3, 4, 7, and 9) and their adaptor molecules MyD88 and IRAK4 are dispensable in cross-priming by a mycobacterial HSP70-antigen (ovalbumin as a model antigen) fusion protein; in contrast, MyD88/IRAK4, but not TLRs, are required for tumor rejection induced by the same reagent. Our results indicate that HSP-mediated cross-priming uses a second signal produced by mechanisms other than TLR cascades. We hypothesize that efficient cross-priming by HSP70 alone is insufficient for tumor rejection and that MyD88/IRAK4-dependent inflammatory stimulation, which might contribute to maintenance of the initially primed effector cells, is required to eradicate tumor burden.
Department of Immunology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Shusaku
S
Mizukami
Chiaki
C
Kajiwara
Masato
M
Tanaka
Tsuneyasu
T
Kaisho
Heiichiro
H
Udono
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045142:Cross-Priming / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000502:physiology*; D009369:Neoplasms / Q000276:immunology*; D010047:Ovalbumin / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology; D051193:Toll-Like Receptors / Q000276:immunology
D018840:HSP70 Heat-Shock Proteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; D010047:Ovalbumin; D053592:Interleukin-1 Receptor-Associated Kinases; C507774:Irak4 protein, mouse