Critical role for CD1d-restricted invariant NKT cells in stimulating intrahepatic CD8 T-cell responses to liver antigen.
OBJECTIVE
V alpha14 invariant natural killer T cells (iNKT) are localized in peripheral tissues such as the liver rather than lymphoid tissues. Therefore, their role in modulating the stimulation of conventional, major histocompatibility complex (MHC)-restricted T-cell responses has remained ambiguous. We here describe a role for V alpha14 iNKT cells in modulating conventional T-cell responses to antigen expressed in liver, using transferrin-mOVA (Tf-mOVA) mice.


METHODS
Naïve ovalbumin-specific class I MHC-restricted T cells (OTI) were adoptively transferred into Tf-mOVA mice in the presence or absence of iNKT-cell agonist alpha-galactosylceramide, after which OTI T-cell priming, antigen-specific cytokine production, cytotoxic killing ability, and liver damage were analyzed.


RESULTS
Transfer of OTI cells resulted in robust intrahepatic, antigen-specific proliferation of T cells. OTI T cells were activated in liver, and antigen-specific effector function was stimulated by coactivation of Valpha14 iNKT cells using alpha-galactosylceramide. This stimulation was absent in CD1d(-/-)Tf-mOVA mice, which lack V alpha14 iNKT cells, and was prevented when interferon-gamma and tumor necrosis factor-alpha production by V alpha14 iNKT cells was blocked.


CONCLUSIONS
CD1d-restricted V alpha14 iNKT cells stimulate intrahepatic CD8 T-cell effector responses to antigen expressed in liver. Our findings elucidate a previously unknown intervention point for targeted immunotherapy to autoimmune and possibly infectious liver diseases.
Department of Dermatology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Dave
D
Sprengers
Fenna C M
FC
Sillé
Katja
K
Derkow
Gurdyal S
GS
Besra
Harry L A
HL
Janssen
Eckart
E
Schott
Marianne
M
Boes
D019264:Adoptive Transfer; D000818:Animals; D000906:Antibodies; D018949:Antigens, CD1 / Q000235:genetics / Q000378:metabolism*; D055610:Antigens, CD1d; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D005699:Galactosylceramides / Q000378:metabolism; D019693:Hepatitis, Autoimmune / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015843:Serpins / Q000235:genetics / Q000378:metabolism*; D014168:Transferrin / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; D018949:Antigens, CD1; D055610:Antigens, CD1d; D005699:Galactosylceramides; D018398:Homeodomain Proteins; D011948:Receptors, Antigen, T-Cell; C085344:SERPIN-B5; D015843:Serpins; D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; C064658:RAG-1 protein; D007371:Interferon-gamma