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Functional Characterization of IL-40 a novel B cell cytokine and Physiological implications of CCL28 ablation


Immune responses are regulated by an intricate balance between cytokine production and actions of various immune cell types. Cytokines are key regulators of the immune system and represent molecular messengers that provide extrinsic cues that direct the genesis of an immune response and its ultimate down-regulation. Here, I aim to characterize two cytokines that play distinct roles in the development of humoral immune responses.

First, I describe a novel B cell cytokine, Interleukin 40 (IL-40) that is expressed in hematopoetic tissues (fetal liver and bone marrow) and by a lymphocyte population not regularly associated with cytokine secretion (activated B cells). Interestingly, the IL-40 gene is only present in mammalian genomes, indicating that it may participate in a mammalian-specific immune function. One such mammalian specific function which is also immune related is the process of lactation. The mammary gland undergoes extensive remodeling upon the onset of lactation. Milk ducts become defined to transport milk and the immune microenvironment undergoes significant changes that lead to the production of IgA. Importantly, IL-40 is up-regulated immediate after lactation. An IL-40 deficient mouse (Il-40-/- mouse), exhibits an altered B cell phenotype, reduced serum and mucosal IgA, and a blunted response to HI-VACV (heat-inactivated vaccinia virus). I next focus on CCL28, a mucosal chemotactic cytokine. CCL28 is responsible for the recruitment of IgA secreting cells to mucosal sites via its receptor CCR10. Additionally, CCL28 is a potent antimicrobial peptide that can inhibit gram positive/gram negative bacteria, and C. albicans. Here, I functionally characterize the first mouse with a targeted deletion of the Ccl28 gene, (Ccl28-/- mouse). The Ccl28-/- mouse exhibits altered levels of IgA in mucosal secretions, and high susceptibility to salmonella infection.

Overall, I have functionally characterized two distinct cytokine knock-out mouse models, IL-40 and CCL28. I predict that through my doctoral work I have laid the foundation for a better understanding of the role that these two cytokines play in the fields of B cell biology, cytokine discovery, mucosal immunology and the pathogenesis of mucosal infections.

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