A Role for CD40-CD40 Ligand Interactions in the Generation of Type 1 Cytokine Responses in Human Leprosy

ABSTRACT Mice of the PERA/Ei strain (PE mice) are highly susceptible to tumor induction by polyomavirus and transmit their susceptibility in a dominant manner in crosses with resistant C57BR/cdJ mice (BR mice). BR mice respond to polyomavirus infection with a type 1 cytokine response and develop effective cell-mediated immunity to the virus-induced tumors. By enumerating virus-specific CD8+ T cells and measuring cytokine responses, we show that the susceptibility of PE mice is due to the absence of a type 1 cytokine response and a concomitant failure to sustain virus-specific cytotoxic T lymphocytes. (PE × BR)F1 mice showed an initial type 1 response that became skewed toward type 2. Culture supernatants of splenocytes from infected PE mice stimulated in vitro contained high levels of interleukin-10 and no detectable gamma interferon, while those from BR mice showed the opposite pattern. Differences in the innate immune response to polyomavirus by antigen-presenting cells in PE mice and BR mice led to polarization of T-cell cytokine responses. Adherent cells from spleens of infected BR mice produced high levels of interleukin-12, while those from infected PE and F1 mice produced predominantly interleukin-10. PE and F1 mice infected by polyomavirus responded with increases in antigen-presenting cells expressing B7.2 costimulatory molecules, whereas BR mice responded with increased expression of B7.1. Administration of recombinant interleukin-12 along with virus resulted in partial protection of PE mice and provided complete protection against tumor development in F1 animals.

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IL-12-Deficient Mice Are Defective in IFNγ Production and Type 1 Cytokine Responses

Immunity ◽

10.1016/s1074-7613(00)80413-6 ◽

1996 ◽

Vol 4 (5) ◽

pp. 471-481 ◽

Cited By ~ 713

Author(s):

Jeanne Magram ◽

Suzanne E Connaughton ◽

Rajeev R Warrier ◽

Daisy M Carvajal ◽

Chang-you Wu ◽

...

Keyword(s):

Cytokine Responses ◽

Type 1 Cytokine ◽

Deficient Mice

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Natural Antibodies Against Bone Morphogenic Proteins and Interferons in Healthy Donors and in Patients with Infections Linked to Type-1 Cytokine Responses

Journal of Interferon & Cytokine Research ◽

10.1089/jir.2010.0075 ◽

2011 ◽

Vol 31 (9) ◽

pp. 661-669 ◽

Cited By ~ 8

Author(s):

Melody Sauerborn ◽

Esther van de Vosse ◽

Diyar Delawi ◽

Jaap T. van Dissel ◽

Vera Brinks ◽

...

Keyword(s):

Natural Antibodies ◽

Bone Morphogenic Proteins ◽

Cytokine Responses ◽

Healthy Donors ◽

Type 1 Cytokine

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IL-12-Deficient Mice Are Defective but Not Devoid of Type 1 Cytokine Responses

Annals of the New York Academy of Sciences ◽

10.1111/j.1749-6632.1996.tb52655.x ◽

1996 ◽

Vol 795 (1 Interleukin 1) ◽

pp. 60-70 ◽

Cited By ~ 77

Author(s):

JEANNE MAGRAM ◽

JESSICA SFARRA ◽

SUZANNE CONNAUGHTON ◽

DENISE FAHERTY ◽

RAJEEV WARRIER ◽

...

Keyword(s):

Cytokine Responses ◽

Type 1 Cytokine ◽

Deficient Mice

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Role of CD40 Ligand Signaling in Defective Type 1 Cytokine Response in Human Immunodeficiency Virus Infection

The Journal of Infectious Diseases ◽

10.1086/320734 ◽

2001 ◽

Vol 183 (12) ◽

pp. 1722-1731 ◽

Cited By ~ 34

Author(s):

Carlos S. Subauste ◽

Matthew Wessendarp ◽

A. George Smulian ◽

Peter T. Frame

Keyword(s):

Human Immunodeficiency Virus ◽

Virus Infection ◽

Human Immunodeficiency Virus Infection ◽

Cd40 Ligand ◽

Cytokine Response ◽

Immunodeficiency Virus ◽

Type 1 Cytokine

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Patent Filarial Infection Modulates Malaria-Specific Type 1 Cytokine Responses in an IL-10-Dependent Manner in a Filaria/Malaria-Coinfected Population

The Journal of Immunology ◽

10.4049/jimmunol.0900257 ◽

2009 ◽

Vol 183 (2) ◽

pp. 916-924 ◽

Cited By ~ 48

Author(s):

Simon Metenou ◽

Benoit Dembélé ◽

Siaka Konate ◽

Housseini Dolo ◽

Siaka Y. Coulibaly ◽

...

Keyword(s):

Dependent Manner ◽

Filarial Infection ◽

Cytokine Responses ◽

Type 1 Cytokine

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Enhanced Interleukin-12 and CD40 Ligand Activities but Reduced Staphylococcus aureus Cowan 1-Induced Responses Suggest a Generalized and Progressively Impaired Type 1 Cytokine Pattern for Human Schistosomiasis

Infection and Immunity ◽

10.1128/iai.70.11.5903-5912.2002 ◽

2002 ◽

Vol 70 (11) ◽

pp. 5903-5912 ◽

Cited By ~ 2

Author(s):

Silvia M. L. Montenegro ◽

Frederico G. C. Abath ◽

Ana Lúcia C. Domingues ◽

Wlademir G. Melo ◽

Clarice N. L. Morais ◽

...

Keyword(s):

Staphylococcus Aureus ◽

T Cell ◽

Cd40 Ligand ◽

Cytokine Expression ◽

Biologically Active ◽

Interleukin 12 ◽

Staphylococcus Aureus Cowan ◽

Antigen Presenting ◽

Type 1 Cytokine

ABSTRACT Whole-blood-cell cultures from schistosomiasis patients were stimulated with a variety of T-cell-dependent and T-cell-independent stimuli to determine whether the defect in type 1 cytokine expression observed following helminth infection is associated with alterations in interleukin-12 (IL-12) or CD40 ligand (CD40L) responsiveness. Cultures from uninfected individuals produced abundant gamma interferon in response to Staphylococcus aureus Cowan 1 (SAC), while patients with intestinal and hepatosplenic disease displayed intermediate and weak responses, respectively. Importantly, the decrease in type 1 cytokine expression was not attributed to defects in IL-12- or CD40L-induced activity. Indeed, schistosomiasis patients displayed heightened responses and even produced more biologically active IL-12 when stimulated with SAC and CD40L than did uninfected controls. Finally, additional studies suggested only a partial role for IL-10, since intestinal patients were the only group that overproduced this downregulatory cytokine. Together, these studies demonstrate that the type 1 deficiency in chronic hepatosplenic schistosomiasis is not related to specific defects in IL-12, IL-10, or CD40L activity, although changes in the functional status of antigen-presenting cells appear to be involved.

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