TAP-1 indirectly regulates CD4+ T cell priming in Toxoplasma gondii infection by controlling NK cell IFN-gamma production.
To investigate if transporter associated with antigen processing (TAP)-1 is required for CD8(+) T cell-mediated control of Toxoplasma gondii in vivo, we compared the resistance of TAP-1(-/-), CD8(-/-), and wild-type (WT) mice to infection with the parasite. Unexpectedly, TAP-1(-/-) mice displayed greater susceptibility than CD8(-/-), beta(2)-microglobulin(-/-) (beta(2)m(-/-)), or WT mice to infection with an avirulent parasite strain. The decreased resistance of the TAP-1(-/-) mice correlated with a reduction in the frequency of activated (CD62L(low) CD44(hi)) and interferon (IFN)-gamma-producing CD4(+) T cells. Interestingly, infected TAP-1(-/-) mice also showed reduced numbers of IFN-gamma-producing natural killer (NK) cells relative to WT, CD8(-/-), or beta(2)m(-/-) mice, and after NK cell depletion both CD8(-/-) and WT mice succumbed to infection with the same kinetics as TAP-1(-/-) animals and displayed impaired CD4(+) T cell IFN-gamma responses. Moreover, adoptive transfer of NK cells obtained from IFN-gamma(+/+), but not IFN-gamma(-/-), animals restored the CD4(+) T cell response of infected TAP-1(-/-) mice to normal levels. These results reveal a role for TAP-1 in the induction of IFN-gamma-producing NK cells and demonstrate that NK cell licensing can influence host resistance to infection through its effect on cytokine production in addition to its role in cytotoxicity.
Goldszmid
Romina S
RS
Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, MD 20892, USA. rgoldszmid@niaid.nih.gov
Bafica
Andre
A
Jankovic
Dragana
D
Feng
Carl G
CG
Caspar
Pat
P
Winkler-Pickett
Robin
R
Trinchieri
Giorgio
G
Sher
Alan
A
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology / Q000469:parasitology; D020022:Genetic Predisposition to Disease; D007371:Interferon-gamma / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D014122:Toxoplasma / Q000254:growth & development / Q000276:immunology*; D014123:Toxoplasmosis / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000276:immunology
D000071181:ATP Binding Cassette Transporter, Subfamily B, Member 2; D018528:ATP-Binding Cassette Transporters; C486171:Tap1 protein, mouse; D001613:beta 2-Microglobulin; D007371:Interferon-gamma