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theses

Tumor necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF family of cytoplasmic adaptor proteins that is ubiquitously expressed in various cell types of the immune system. It is shared for signaling by a variety of adaptive and innate immune receptors as well as cytokine receptors. Previous studies examining conditional TRAF3-deficient mouse models that have the traf3 gene specifically deleted in B lymphocytes or T lymphocytes have revealed the diverse and critical in vivo functions of TRAF3 in adaptive immunity. Although in vitro evidence points to a pivotal and indispensable role for TRAF3 in type I interferon production induced by pattern recognition receptors in macrophages and dendritic cells, the in vivo functions of TRAF3 in myeloid cells had long remained unclear. My dissertation research has addressed this gap in knowledge by generating and characterizing myeloid cell-specific TRAF3-deficient (M-TRAF3-/-) mouse model, which allowed us to gain insights into the in vivo functions of TRAF3 in myeloid cells. We found that TRAF3 ablation did not affect the maturation or homeostasis of myeloid cells in young adult mice, even though TRAF3-deficient macrophages and neutrophils exhibited constitutive NF-B2 activation. However, in response to injections with LPS (a bacterial mimic) or polyI:C (a viral mimic), M-TRAF3 /- mice exhibited an altered profile of cytokine production. M-TRAF3 /- mice immunized with T cell-independent (TI) and -dependent (TD) antigens displayed elevated TI IgG3 as well as TD IgG2b responses. Interestingly, 15-22 months old M-TRAF3-/- mice spontaneously developed chronic inflammation and tumors including TRAF3-sufficient B lymphoma and hepatocellular adenoma and TRAF3-deficient histiocytic sarcoma. Moreover, diseased M-TRAF3 /- mice displayed expanded population of myeloid derived suppressor cells that were highly immunosuppressive and blocked the proliferation of CD8 T cells in vitro. To further investigate the role of TRAF3 in MDSC physiology, we developed a new chronic inflammatory model in young adult M-TRAF3-/- mice using repeated injections of heat-killed BCG. Our results obtained from this model established TRAF3 as a suppressor of MDSC expansion and showed that chronic inflammation led to greater de novo synthesis of MDSC in the spleen of M-TRAF3-/- mice as compared to littermate control mice. In addition, characterization of B lymphomas spontaneously developed in aging M-TRAF3 /- mice confirmed their germinal center or post-germinal center origin as they displayed somatic hypermutations and had undergone Ig isotype switching. Interestingly, we discovered reactivation of endogenous retroviruses in these B lymphomas. Furthermore, we found that antibiotic treatment of mice prevents chronic inflammation and B lymphoma development in aging M-TRAF3-/- mice, indicating the requirement of commensal bacteria for the development of chronic inflammation and B lymphomas in these mice. Importantly however, antibiotic treatment did not affect the development of histiocytic sarcomas in aging M-TRAF3-/- mice, demonstrating a cell intrinsic role of TRAF3 in suppressing the oncogenesis of this tumor type. Taken together, the results from my dissertation research has established myeloid cell TRAF3 as a critical regulator of innate immune responses and a potent inhibitor of chronic inflammation, MDSC expansion and tumor development. Our findings suggest that restoration of TRAF3 signaling pathways in myeloid cells could be a potential therapeutic strategy for the treatment of a variety of human diseases, including chronic inflammatory diseases, chronic infectious diseases and cancers.

ETD_7778

Ph.D.

Includes bibliographical references

by Almin Iqbalali Lalani

doi:10.7282/T3668GMX

ETD doctoral

The author owns the copyright to this work.