Year of Award

2019

Document Type

Dissertation

Degree Type

Doctor of Philosophy (PhD)

Degree Name

Biomedical Sciences

Other Degree Name/Area of Focus

Immunology

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Scott Wetzel

Commitee Members

Jesse Hay, Mike Minnick, Kevan Roberts, Dave Shepherd

Keywords

CD4+, Differentiation, Signaling, Trogocytosis

Abstract

Trogocytosis is the direct intercellular transfer of membrane and membrane associated molecules. Unlike other passive-membrane transfer events, trogocytosed molecules may remain fully functional and become re-expressed on the surface of the trogocytosis-positive (trog+) recipient. This phenomenon commonly occurs between various cell types, including those of the immune system. CD4+ T cell trogocytosis occurs during their activation by antigen presenting cells (APC). Consequently, the acquired molecules include ligands for signaling receptors on the T cell.

The impacts of CD4+ trogocytosis on the immune response are largely unknown. While it has been demonstrated that trog+ cells can present trogocytosed peptide:MHC (pMHC), and costimulatory molecules to activate other T cells, the consequences of trogocytosis on the individual trog+ CD4+ T cell have not been studied in-depth. We previously reported that trog+ cells perform cell-autonomous signaling by trogocytosed ligands engaging surface receptors, referred here to as trogocytosis-mediated signaling. This signaling led to the enhanced survival of trog+ cells in vitro compared to trog– cells after APC removal. Because the duration of T cell signaling influences the activation, lineage determination, and effector functionality of CD4+ T cells; trogocytosis-mediated signaling has the potential to uniquely modulate the effector-cytokine production and differentiation of trog+ CD4+ T cell after separation from APC.

Examining this possibility is the foundation for this dissertation. Here, I will report my findings that: 1. Between 0-72 hrs post-separation from APC, trogocytosis-mediated signaling drives IL-4 and GATA-3 expression, consistent with T helper type-2 (TH2) differentiation; 3. Extended trogocytosis-mediated signaling (>72 hrs) leads to the expression of Bcl-6, PD-1, CXCR5, and IL-21, consistent with T follicular helper (TFH) differentiation; 4. In absence of exogenous antigen (Ag), trogocytosis-mediated signaling is critical for the survival of the activated CD4+ T cells with high memory-potential.

Despite the critical role for CD4+ T cells in generating protective immunity in the host, much remains unknown about the differentiation of CD4+ T cell effector subsets. The findings here present a novel mechanism for CD4+ T cell activation and differentiation via trogocytosis-mediated signaling, demonstrating the broad implications for such signaling in matters of public health.

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© Copyright 2019 Steven James Reed