Circulating soluble CD4 directly prevents host resistance and delayed-type hypersensitivity response to Cryptococcus neoformans in mice.
In the present study, we examined the effect of soluble CD4 (sCD4) on host resistance and delayed-type hypersensitivity (DTH) response to Cryptococcus neoformans using a novel mutant mouse that exhibits a defect in the expression of membrane-bound CD4 but secretes high levels of sCD4 in the serum. In these mice, host resistance to this pathogen was impaired as indicated by an increased number of live pathogens in the lung. To elucidate the mechanism of immunodeficiency, three different sets of experiments were conducted. First, administration of anti-CD4 mAb restored the attenuated host defense. Second, in CD4 gene-disrupted (CD4KO) mice, host resistance was not attenuated compared to control mice. Third, implantation of sCD4 gene-transfected myeloma cells rendered the CD4KO mice susceptible to this infection, while similar treatment with mock-transfected cells did not show such an effect. These results indicated that immunodeficiency in the mutant mice was attributed to the circulating sCD4 rather than to the lack of CD4+ T cells. In addition, DTH response to C. neoformans evaluated by footpad swelling was reduced in the mutant mice compared to that in the control, and the reduced response was restored by the administration of anti-CD4 mAb. Finally, serum levels of IFN-gamma, IL-12 and IL-18 in the mutant mice were significantly reduced, while there was no difference in Th2 cytokines, such as IL-4 and IL-10. Considered collectively, our results demonstrated that sCD4 could directly prevent host resistance and DTH response to C. neoformans through interference with the production of Th1-type cytokines.
Kawakami
K
K
The First Department of Internal Medicine, Faculty of Medicine, University of the Ryukyus, Nishihara, Okinawa, Japan. kawakami@med.u-ryukyu.ac.jp
Koguchi
Y
Y
Qureshi
M H
MH
Yara
S
S
Kinjo
Y
Y
Miyazato
A
A
Nishizawa
A
A
Nariuchi
H
H
Saito
A
A
D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology*; D003453:Cryptococcosis / Q000097:blood / Q000276:immunology; D003455:Cryptococcus neoformans / Q000276:immunology*; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology; D007371:Interferon-gamma / Q000097:blood; D018664:Interleukin-12 / Q000097:blood; D020382:Interleukin-18 / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012995:Solubility
D015704:CD4 Antigens; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma