Immunosenescence in TCR-Transgenic Bone Marrow Chimeras

Rider University, Lawrenceville NJ

Investigators

Linked publications, trials & patents

Abstract

DESCRIPTION (provided by the applicant): Study of the effects of aging upon the frequencies and functions of Ag-specific immune responses in vivo have been complicated by very low numbers of Ag-specific T-cells. TCR-transgenic (tgic) mice circumvent this problem; however, they fail to respond normally to immunization due to their unusually high number of Ag-specific T-cells. This experimental constraint has led us to propose a model that will allow a detailed assessment of Ag-specific naive and memory CD4+ T-cell responses in vivo under more physiological conditions. Mixed bone marrow (BM) chimeras will be constructed using BALB/c and DO11.1O TCR-tgic mice as BM donors and severe-combined immune-defective (SCID) mice as recipients. By changing the ratio of DOl1.lO:BALB/c BM we will generate mice with readily detectable numbers of TCR-tgic CD4+ cells in the context of normal leukocytes generated from the BALB/c BM. We anticipate that this model will circumvent two problems evident in the literature: i) poor responses of TCR-tgic mice to in vivo immunization, and ii) the inability of TCR-tgic CD4+ T-cells to persist after their adoptive transfer into normal mice. There will be three specific aims to this research plain: Aim I. Develop the Model: The optimal ratio of DOl1.10 and BALB/c BM for engraftment and T-cell development will be determined. Readouts for lymphocyte function will be developed with young chimeras. With these data, a colony of chimeras will be established for the aging studies in Aim 3. Aim 2. Effects of memory T-cell poor composition upon the activation of naive CD4+ T-cells: Protocols that generate an "aged" T-cell pool in young mice will be tested. To increase the number of nontgic memory T-cells, superantigen challenge and chimera construction using aged recipients will be studied. The impact of memory T-cells upon naive T-cell biology will be studied in these mice. Aim 3. Effects of aging on naive and short- and long-term memory CD4+ T-cells: Longitudinal analyses of naive and memory tgic T-cell number in unimmunized and primed chimeras will be performed as mice age. Ag-specific primary and secondary responses in vitro and in vivo will be assessed throughout lifespan. These approaches will contribute to an understanding of the effects of aging on the frequency and function of naive and short- and long-term memory cells in vivo. The information generated by these studies will contribute to the rational design of vaccines that will better target naive cells and enhance the persistence and response of memory cells in the elderly.