Vaccine-induced antibody isotypes are skewed by impaired CD4 T cell and invariant NKT cell effector responses in MyD88-deficient mice.
The requirement for TLR signaling in the initiation of an Ag-specific Ab response is controversial. In this report we show that a novel OVA-expressing recombinant Salmonella vaccine (Salmonella-OVA) elicits a Th1-biased cell-mediated and serum Ab response upon oral or i.p. immunization of C57BL/6 mice. In MyD88(-/-) mice, Th1-dependent Ab responses are greatly reduced while Th2-dependent Ab isotypes are elevated in response to oral and i.p., but not s.c. footpad, immunization. When the T effector response to oral vaccination is examined we find that activated, adoptively transferred Ag-specific CD4(+) T cells accumulate in the draining lymph nodes, but fail to produce IFN-gamma, in MyD88(-/-) mice. Moreover, CD1d tetramer staining shows that invariant NKT cells are activated in response to oral Salmonella-OVA vaccination in wild-type, but not MyD88(-/-), mice. Treatment with neutralizing Ab to CD1d reduces the OVA-specific Ab response only in MyD88-sufficient wild-type mice, suggesting that both Ag-specific CD4 T cell and invariant NKT cell effector responses to Salmonella-OVA vaccination are MyD88 dependent. Taken together, our data indicate that the type of adaptive immune response generated to this live attenuated vaccine is regulated by both the presence of MyD88-mediated signals and vaccination route, which may have important implications for future vaccine design.
Iweala
Onyinye I
OI
Center for Immunology and Inflammatory Disease, Division of Rheumatology, Massachusetts General Hospital, Charlestown, MA 02129, USA.
Smith
Donald W
DW
Matharu
Kabir S
KS
Sada-Ovalle
Isabel
I
Nguyen
Deanna D
DD
Dekruyff
Rosemarie H
RH
Umetsu
Dale T
DT
Behar
Samuel M
SM
Nagler
Cathryn R
CR
D000284:Administration, Oral; D000818:Animals; D000907:Antibodies, Bacterial / Q000096:biosynthesis* / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis* / Q000097:blood; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D022562:Salmonella Vaccines / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D051193:Toll-Like Receptors / Q000502:physiology; D014613:Vaccines, Attenuated / Q000008:administration & dosage / Q000276:immunology; D014614:Vaccines, Synthetic / Q000008:administration & dosage / Q000276:immunology
D000907:Antibodies, Bacterial; D007132:Immunoglobulin Isotypes; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D022562:Salmonella Vaccines; D051193:Toll-Like Receptors; D014613:Vaccines, Attenuated; D014614:Vaccines, Synthetic