Cytokine signaling control of naïve CD8⁺ T-cell homeostasis

Mounting effective adaptive immune responses requires a large naive T-cell population with a wide diversity of target specificity. Naive CD8⁺ T-cells depend on T-Cell Receptor (TCR) and ye cytokine signals for their homeostatic survival and proliferation, but differences in sensitivity to these homeostatic signals among T-cell clones have been generally attributed to differences in TCR specificity. This thesis describes the novel identification and characterization of intrinsic heterogeneity in the TCR-independent abilities of CD8⁺ T-cells to respond to homeostatic ye cytokines, and survive in their absence. These differences were predictably marked by expression of CD5, a surrogate marker of TCR:spMHC binding avidity. In vitro, CD5I T-cells proliferate more robustly to saturating levels of the y, interleukin (IL) cytokines IL-7, IL-2 and IL-15, while CD5" cells have prolonged survival in the absence of dedicated homeostatic cues. IL-7 is the most critical cytokine for naive T-cell homeostasis, and a detailed analysis of IL-7 signaling revealed that IL-7 responsiveness is primarily determined by IL-7 receptor (IL-7R) expression, which is correlated with CD5 expression. While T-cells share common relationships between IL-7-induced signaling and responses, the signaling network encodes distinct signaling requirements for survival, proliferation and CD8a induction responses. As a result, all T-cells survive when treated with high doses of IL-7, but only cells with a critically high level of IL-7R expression can induce sufficient signaling to proliferate. IL-7 depletion also scales with IL-7R expression, and the 'overconsumption' of IL-7 by CD5hiIL-7Rh T-cells can compromise their prolonged survival. In vivo, lymphoreplete mice preserve the homeostatic diversity of CD5 expression by maintaining physiological IL-7 levels that promote neither preferential proliferation nor survival of CD5hiIL-7Rh' and CD5'"IL-7R'" T-cells. However, elevated IL-7 levels in lymphopenic mice or lymphoreplete mice administered with exogenous IL-7 yield preferential expansion of CD5hiIL-7Rh T-cell subsets, elevating the mean CD5 expression of the T-cell repertoire. This demonstration of functional intrinsic heterogeneities in IL-7R expression between CD8⁺ T-cells supports a previously under-appreciated role for IL-7 in maintaining not only the size but also the diversity of the T-cell repertoire. Furthermore, the exemplified potential for preferential expansion of more auto-reactive CD5"I T-cells subsets has important implications for the design of cytokine therapies.

Department dc:contributor.department

Massachusetts Institute of Technology. Dept. of Biological Engineering.

Grantor dc:publisher

Massachusetts Institute of Technology

Year dc:date.issued

2010

Author dc:creator

• Palmer, Megan Joan

Advisor dc:contributor.advisor

• Douglas A. Lauffenburger.

• Biological Engineering.

Statement dc:rights

• MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission.

Licence dc:rights.uri

• http://dspace.mit.edu/handle/1721.1/7582

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/1721.1/60786

OAI identifier oai:identifier

oai:dspace.mit.edu:1721.1/60786