IFN-gamma-inducible protein 10 (IP-10; CXCL10)-deficient mice reveal a role for IP-10 in effector T cell generation and trafficking.
IFN-gamma-inducible protein 10 (IP-10, CXCL10), a chemokine secreted from cells stimulated with type I and II IFNs and LPS, is a chemoattractant for activated T cells. Expression of IP-10 is seen in many Th1-type inflammatory diseases, where it is thought to play an important role in recruiting activated T cells into sites of tissue inflammation. To determine the in vivo function of IP-10, we constructed an IP-10-deficient mouse (IP-10(-/-)) by targeted gene disruption. Immunological analysis revealed that IP-10(-/-) mice had impaired T cell responses. T cell proliferation to allogeneic and antigenic stimulation and IFN-gamma secretion in response to antigenic challenge were impaired in IP-10(-/-) mice. In addition, IP-10(-/-) mice exhibited an impaired contact hypersensitivity response, characterized by decreased ear swelling and reduced inflammatory cell infiltrates. T cells recovered from draining lymph nodes also had a decreased proliferative response to Ag restimulation. Furthermore, IP-10(-/-) mice infected with a neurotropic mouse hepatitis virus had an impaired ability to control viral replication in the brain. This was associated with decreased recruitment of CD4(+) and CD8(+) lymphocytes into the brain, reduced levels of IFN-gamma and the IFN-gamma-induced chemokines monokine induced by IFN-gamma (Mig, CXCL9) and IFN-inducible T cell alpha chemoattractant (I-TAC, CXCL11) in the brain, decreased numbers of virus-specific IFN-gamma-secreting CD8(+) cells in the spleen, and reduced levels of demyelination in the CNS. Taken together, our data suggest a role for IP-10 in both effector T cell generation and trafficking in vivo.
Dufour
Jennifer H
JH
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Dziejman
Michelle
M
Liu
Michael T
MT
Leung
Josephine H
JH
Lane
Thomas E
TE
Luster
Andrew D
AD
D000818:Animals; D000941:Antigens / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002465:Cell Movement / Q000235:genetics* / Q000276:immunology*; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000172:deficiency* / Q000235:genetics / Q000502:physiology*; D018352:Coronavirus Infections / Q000235:genetics / Q000276:immunology; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D003877:Dermatitis, Contact / Q000235:genetics / Q000517:prevention & control; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D004679:Encephalomyelitis / Q000235:genetics / Q000276:immunology; D006131:Growth Inhibitors / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics* / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D006517:Murine hepatitis virus / Q000276:immunology; D016297:Mutagenesis, Site-Directed; D010047:Ovalbumin / Q000276:immunology / Q000494:pharmacology; D013154:Spleen / Q000276:immunology / Q000473:pathology
D000941:Antigens; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D006131:Growth Inhibitors; D007519:Isoantigens; D007371:Interferon-gamma; D010047:Ovalbumin