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CD4+ T cell Production of IL-10 and Regulation of Immune Responses in Aging

Almanan, Maha
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535466924008943

Abstract Details

2018, PhD, University of Cincinnati, Medicine: Immunology.
The immune system plays a vital role in the protection against invading pathogens. A successful immune response is dictated by the fine balance between pro- and anti-inflammatory mediators. With age the immune system undergoes a progressive dysregulation due to the dramatic reduction in the naive T cell pool, a relative clonal expansion of memory T cells as well as accumulation of regulatory T cells. Another aspect of this immune dysregulation is the persistent, low grade inflammation that develops with age and is referred to as (inflammaging). Together, dysfunctional immune responses and inflammaging are a great risk for serious age-related pathologies. Thus, understanding the mechanisms regulating this age-related immune dysfunction is critical for healthy aging. Viral infections including latent cytomegalovirus (CMV) are thought to be one of driving forces of age-related alterations in immune function and inflammaging. While T cell responses are critical against CMV infection, the regulatory mechanisms that control latency are not well understood. Regulatory T cells are known to accumulate with age, likely due to their enhanced survival. While Treg accumulated with age, their per cell functionality remains controversial and possibly model dependent. Treg cells are important regulators of acute infections (including CMV). However, the impact of Treg on latent CMV is unclear. In chapter 3 we aimed at investigating the role of Foxp3+ regulatory T cells (Treg) in latent murine cytomegalovirus (MCMV) infection. We show that Treg played divergent roles in the control of MCMV infection. In the spleen, Treg antagonize CD8+ T cell effector function and promote viral persistence, while in the salivary gland Treg prevent IL-10 production from Foxp3- CD4+ T cells and limit viral reactivation and replication. Together, work in chapter 3 broadens our understanding of the homeostasis and functions of regulatory T cells and IL-10 with age. Our discovery that Treg control IL-10 during latent CMV infection was intriguing. IL-10 is a known regulatory cytokine, playing a major role in shaping immune responses and regulating excessive inflammation. Thus, IL-10 may contribute to counter-regulation of age-driven inflammation. In chapter 4 of this dissertation, we aimed to investigate the role of IL-10 with age and further understand the cellular and molecular mechanisms underlying its production. We provide evidence that aging favors the accrual of CD4+ Foxp3- IL-10+ T cells. Additionally, T follicular helper cells (Tfh) were major producers of IL-10 in aged humans and mice which we have designated as Tfh10 cells. Interestingly, both IL-21 and IL-6 were indispensable for the accumulation of Tfh10 cells with age. Finally, the loss of BCL6 in Foxp3- CD4+ T cells enhanced the production of IL-10 with age. Results from this study highlight the dynamic regulatory/counter-regulatory balance controlling age-related inflammation. More importantly, we show that despite age-driven intrinsic defects in adaptive immune responses, blockade of IL-10 signaling is largely sufficient to restore germinal center (GC) B cell responses in aged mice. Together work from chapter 3 and 4 underscores the complexity of the unique age-related regulatory networks that shape immune responses to latent infections, as well as vaccines.
David Hildeman, Ph.D. (Committee Chair)
Rhonda Cardin, Ph.D. (Committee Member)
Claire Chougnet, Ph.D. (Committee Member)
Kasper Hoebe, Ph.D. (Committee Member)
Kris Steinbrecher, Ph.D. (Committee Member)
231 p.
Immunology

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Citations

  • Almanan, M. (2018). CD4+ T cell Production of IL-10 and Regulation of Immune Responses in Aging [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535466924008943

    APA Style (7th edition)

  • Almanan, Maha. CD4+ T cell Production of IL-10 and Regulation of Immune Responses in Aging. 2018. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535466924008943.

    MLA Style (8th edition)

  • Almanan, Maha. "CD4+ T cell Production of IL-10 and Regulation of Immune Responses in Aging." Doctoral dissertation, University of Cincinnati, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1535466924008943

    Chicago Manual of Style (17th edition)

ucin1535466924008943
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This open access ETD is published by University of Cincinnati and OhioLINK.