Title

The relative contributions of antigen versus interleukin-7 and interleukin-15 during the transition of effector CD8+ T cells from cytotoxic T lymphocytes to memory cells

Date of Award

2007

Availability

Article

Degree Name

Doctor of Philosophy (Ph.D.)

Department

Microbiology and Immunology

First Committee Member

Thomas R. Malek, Committee Chair

Abstract

During an immune response it is difficult to study the kinetics and requirements for memory CD8+ T cell generation because memory cells are best detected after the contraction phase and antigen clearance. To overcome these limitations, we modeled the CTL to memory transition in vitro and following adoptive transfer. In vitro generated CTL cultured for 2 days with IL-2, in the absence of antigen, resulted in the expansion of CTL, whereas culture in IL-7 or IL-15 promoted the development and expansion of central memory-like cells. Memory cell conversion occurred at a low antigen dose that selectively induced a recall response, but not at a higher dose that activated naive cells. Upon adoptive transfer to antigen-free hosts, a small population of in vitro generated CTL engrafted, proliferated extensively, and rapidly acquired properties of memory cells by 3 days post-transfer. In tumor-bearing hosts, CTL converted to memory cells during an anti-tumor response. Since IL-7 and IL-15 have been implicated in the development and homeostasis of memory cells, we generated IL-7Ralpha-deficient mice. Similar to naive OT-I cells, IL-7Ralpha-deficient OT-I cells differentiated into CTL when primed with antigen and IL-2, and upon further culture with IL-15 developed into memory-like cells. The few engrafting IL-7Ralpha-deficient OT-I cells converted to memory-like cells in both normal and IL-15-deficient hosts. In this study we demonstrated the rapid generation of memory cells without the complete removal of antigen. Moreover, there is a permissive dose of antigen for memory cell development. In our system, this permissive dose was correlated to a level of antigen that selectively induced a recall response, but was not sufficient to activate naive cells. The expression of IL-7Ralpha was not required for the conversion from CTL to memory cells. Furthermore, IL-7 and IL-15 function non-redundantly in the maintenance memory CD8 + T cells.

Keywords

Health Sciences, Immunology

Link to Full Text

http://access.library.miami.edu/login?url=http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3285368