Proliferation of CD4+ T cells in response to self and non-self antigens. Role in memory formation

Hrefna Gudmundsdottir, University of Pennsylvania

Abstract

The goal of this thesis project was to determine the role of peptides (self vs. non-self) and CD28 signaling on proliferation and differentiation of responding CD4⁺ T cells into effector and memory cells in vivo. For this purpose, we used murine TCR transgenic CD4 ⁺ T cells that recognize chicken ovalbumin peptide (OVAp). The cells were adoptively transferred into either syngeneic wild type mice followed by immunization with OVAp or into lymphopenic mice, where proliferation occurs due to encounter with self-peptides. Proliferation, in the presence or absence of CD28 costimulation, was measured by labeling the T cells with a bright fluorochrome dye, CFSE, prior to adoptive transfer. Subsequently, proliferative history, cytokine production and capacity for memory were compared. ^ CD28 augmented the proliferative response of CD4⁺ T cells following stimulation with the non-self peptide (OVAp), by increasing both the number of antigen-specific T cells that initiated division, as well as increasing the number of cell divisions. Differentiation into effector cells was cell cycle dependent, as the appearance of surface memory phenotype (CD44-hi, CD45RB-low, CD62L-low) and production of cytokines IL-2 and IFN-γ, correlated with division cycle, independent of costimulation. Thus, CD28 signals enhanced production of IL-2 and IFN-γ by augmenting proliferation of responding T cells. ^ Encounters with self-peptides generated two discrete populations of T cells. One, which was highly proliferative and dependent on CD28 signaling, and the other which contained cells undergoing low levels of CD28-independent proliferation. Interestingly, following encounters with self-peptides, the responding CD4⁺ T cells never became effector cells as they remained small and did not upregulate early activation marker CD69. Yet, these cells acquired phenotypic and functional characteristics of memory cells, indicating that naïve CD4⁺ T cells can differentiate directly into memory cells. ^ These results indicate that optimal proliferative responses of antigen-specific CD4⁺ T cells in response to either self or non-self peptides was dependent on CD28 signals. Differentiation into effector cells required stimulation by the exogenous peptide and correlated best with cell cycle progression and not CD28 signals. Finally, following encounters with self-peptides naïve cells differentiated directly into memory T cells. ^

Subject Area

Biology, Molecular|Health Sciences, Immunology

Recommended Citation

Hrefna Gudmundsdottir, "Proliferation of CD4+ T cells in response to self and non-self antigens. Role in memory formation" (January 1, 2001). Dissertations available from ProQuest. Paper AAI3003632.
http://repository.upenn.edu/dissertations/AAI3003632