Rapid IL-4 production by Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells in resistant mice treated once with anti-IL-12 or -IFN-gamma antibodies at the onset of infection with Leishmania major instructs Th2 cell development, resulting in nonhealing lesions.
Rapid production of IL-4 by Leishmania homolog of mammalian RACK1 (LACK)-reactive CD4(+) T cells expressing the V beta 4-V alpha 8 TCR chains has been shown to drive aberrant Th2 cell development and susceptibility to Leishmania major in BALB/c mice. In contrast, mice from resistant strains fail to express this early IL-4 response. However, administration of either anti-IL-12 or -IFN-gamma at the initiation of infection allows the expression of this early IL-4 response in resistant mice. In this work we show that Leishmania homolog of mammalian RACK1-reactive CD4(+) T cells also expressing the V beta 4-V alpha 8 TCR chains are the source of the early IL-4 response to L. major in resistant mice given anti-IL-12 or -IFN-gamma Abs only at the onset of infection. Strikingly, these cells were found to be required for the reversal of the natural resistance of C57BL/6 mice following a single administration of anti-IL-12 or -IFN-gamma Abs. Together these results suggest that a deficiency in mechanisms capable of down-regulating the early IL-4 response to L. major contributes to the exquisite susceptibility of BALB/c mice to L. major.
Launois
Pascal
P
World Health Organization Immunology Research and Training Center, Institute of Biochemistry, University of Lausanne, Lausanne, Switzerland.
Gumy
Alain
A
Himmelrich
Hayo
H
Locksley
Richard M
RM
Röcken
Martin
M
Louis
Jacques A
JA
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000953:Antigens, Protozoan; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D016207:Cytokines / Q000037:antagonists & inhibitors*; D018450:Disease Progression; D005260:Female; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology; D018664:Interleukin-12 / Q000037:antagonists & inhibitors / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D007700:Kinetics; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015800:Protozoan Proteins / Q000494:pharmacology*; D012333:RNA, Messenger / Q000096:biosynthesis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000032:analysis / Q000235:genetics; D018418:Th2 Cells / Q000276:immunology
D000906:Antibodies; D000953:Antigens, Protozoan; D016207:Cytokines; D015800:Protozoan Proteins; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; C093139:LACK antigen, Leishmania; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma