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dc.contributor.authorGerber, Allison
dc.date.accessioned2021-09-02T16:53:35Z
dc.date.available2021-09-02T16:53:35Z
dc.date.issued2021
dc.identifier.urihttp://hdl.handle.net/10713/16537
dc.descriptionBiochemistry
dc.descriptionUniversity of Maryland, Baltimore
dc.descriptionPh.D.
dc.description.abstractCytokines are critical mediators used by immune cells to communicate as well as protect. The IL-12 family of cytokines are made up of  and  subunits typically assembled within one cell and secreted as a heterodimer. IL-12p40 is the shared β-subunit for both IL-12 (paring with IL-12p35) and IL-23 (with IL-23p19). However, the IL-12p40 monomer is often secreted in excess during infections, but its biological role was not known. In this thesis we investigated the function of secreted IL-12p40 monomer in vivo with the central hypothesis that the monomer combines with multiple α-subunits in vivo to generate IL-12 as well as other heterodimeric cytokines. Consistent with this hypothesis, in chimeric mice containing mixtures of cells that can only express either IL-12p40 or IL-12p35, but not both together, we found that functionally active IL-12 was generated. This alternate two-cell pathway requires IL-12p40 from hematopoietic cells to extracellularly associate with IL-12p35 from radiation-resistant cells. The two-cell mechanism was sufficient to influence local T cell differentiation in sites distal to the initial infection and helped control systemic dissemination of a pathogen although not parasite burden at the site of infection. Broadly, this suggests that early secretion of IL-12p40 monomers by sentinel cells at the infection site may help prepare distal host tissues for potential pathogen arrival. In addition to this role in generating IL-12 through two-cell assembly, we found that IL-12p40 has a novel partner protein, CD5L. This novel heterodimer was present in the serum of uninfected mice, with differences in the basal levels between B6 and Balb/c animals, with Balb/c having higher amounts of p40-CD5L. Functionally, we found that treatment with p40-CD5L leads to IL-4 and IL-10 production by T cells. Taken together, this thesis offers at least two major fundamental advances in cytokine biology – one the concept of a two-cell assembled cytokine and second the identity of a novel TH2-promoting heterodimeric cytokine. The first has significance in immunotherapy and understanding immunity to tissue-specific modulation of immune responses. The second is expected to drive significant research on allergy, responses to parasites and immune deviation.
dc.subjectIL-12
dc.subjectIL-12p40en_US
dc.subjectT cellen_US
dc.subject.meshCytokinesen_US
dc.subject.meshInterleukin-12en_US
dc.subject.meshInterleukin-12 Subunit p40en_US
dc.subject.meshT-Lymphocytesen_US
dc.titleMonomeric IL-12p40 binds partner proteins to modulate immune cell functionen_US
dc.typedissertationen_US
dc.date.updated2021-08-31T22:06:53Z
dc.language.rfc3066en
dc.contributor.advisorSingh, Nevil
dc.contributor.orcid0000-0001-9442-3255en_US
refterms.dateFOA2021-09-02T16:53:36Z


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