alpha(4)beta(7) independent pathway for CD8(+) T cell-mediated intestinal immunity to rotavirus.
Rotavirus (RV), which replicates exclusively in cells of the small intestine, is the most important cause of severe diarrhea in young children worldwide. Using a mouse model, we show that expression of the intestinal homing integrin alpha(4)ss(7) is not essential for CD8(+) T cells to migrate to the intestine or provide immunity to RV. Mice deficient in ss7 expression (ss7(-/-)) and unable to express alpha(4)ss(7) integrin were found to clear RV as quickly as wild-type (wt) animals. Depletion of CD8(+) T cells in ss7(-/-) animals prolonged viral shedding, and transfer of immune ss7(-/-) CD8(+) T cells into chronically infected Rag-2-deficient mice resolved RV infection as efficiently as wt CD8(+) T cells. Paradoxically, alpha(4)ss(7)(hi) memory CD8(+) T cells purified from wt mice that had been orally immunized cleared RV more efficiently than alpha(4)ss(7)(low) CD8(+) T cells. We explained this apparent contradiction by demonstrating that expression of alpha(4)ss(7) on effector CD8(+) T cells depends upon the site of initial antigen exposure: oral immunization generates RV-specific CD8(+) T cells primarily of an alpha(4)ss(7)(hi) phenotype, but subcutaneous immunization yields both alpha(4)ss(7)(hi) and alpha(4)ss(7)(low) immune CD8(+) T cells with anti-RV effector capabilities. Thus, alpha(4)ss(7) facilitates normal intestinal immune trafficking to the gut, but it is not required for effective CD8(+) T cell immunity.
Kuklin
N A
NA
Department of Microbiology and Immunology, Department of Pathology, Stanford University School of Medicine, Stanford, California, USA. nelly_kuklin@merck.com
Rott
L
L
Darling
J
J
Campbell
J J
JJ
Franco
M
M
Feng
N
N
Müller
W
W
Wagner
N
N
Altman
J
J
Butcher
E C
EC
Greenberg
H B
HB
D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002634:Chemotaxis, Leukocyte; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D005243:Feces / Q000821:virology; D005434:Flow Cytometry; D017353:Gene Deletion; D007070:Immunoglobulin A / Q000276:immunology; D007150:Immunohistochemistry; D016023:Integrins / Q000235:genetics / Q000502:physiology*; D007371:Interferon-gamma / Q000378:metabolism; D007421:Intestine, Small / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012401:Rotavirus / Q000276:immunology* / Q000502:physiology; D012400:Rotavirus Infections / Q000276:immunology* / Q000821:virology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D017201:Virus Shedding
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D016023:Integrins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; C071777:integrin alpha4beta7; D007371:Interferon-gamma