{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/60786"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/60786","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"Cytokine signaling control of naïve CD8⁺ T-cell homeostasis","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Palmer, Megan Joan"],"institution":"Massachusetts Institute of Technology","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Dept. of Biological Engineering.","school":null,"contributors":[],"advisors":["Douglas A. Lauffenburger."],"committee_chairs":[],"committee_members":[],"year":2010,"date_issued":"2010","date_published":"2010","updated_at":"2026-07-22T22:21:41Z","subjects":["Biological Engineering."],"languages":["eng"],"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."],"rights_urls":["http://dspace.mit.edu/handle/1721.1/7582"],"identifier_entries":[]},"links":{"outbound_url":"http://hdl.handle.net/1721.1/60786","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Douglas A. Lauffenburger."]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. Dept. of Biological Engineering."]},{"key":"dc:contributor.other","label":"Dc Contributor Other","values":["Massachusetts Institute of Technology. Dept. of Biological Engineering."]},{"key":"dc:creator","label":"Author","values":["Palmer, Megan Joan"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2011-01-26T14:24:08Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2011-01-26T14:24:08Z"]},{"key":"dc:date.issued","label":"Date","values":["2010"]},{"key":"dc:publisher","label":"Institution","values":["Massachusetts Institute of Technology"]},{"key":"dc:type","label":"Dc Type","values":["Thesis"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Biological Engineering."]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["eng"]},{"key":"dc:rights","label":"Dc Rights","values":["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."]},{"key":"dc:rights.uri","label":"Rights URI","values":["http://dspace.mit.edu/handle/1721.1/7582"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["http://hdl.handle.net/1721.1/60786"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description","label":"Description","values":["Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2010.","Cataloged from PDF version of thesis.","Includes bibliographical references (p. 191-209)."]},{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["Cytokine signaling control of naïve CD8⁺ T-cell homeostasis"]}]}],"canonical_facts":{"dc:contributor.advisor":["Douglas A. Lauffenburger."],"dc:contributor.department":["Massachusetts Institute of Technology. Dept. of Biological Engineering."],"dc:contributor.other":["Massachusetts Institute of Technology. Dept. of Biological Engineering."],"dc:creator":["Palmer, Megan Joan"],"dc:date.accessioned":["2011-01-26T14:24:08Z"],"dc:date.available":["2011-01-26T14:24:08Z"],"dc:date.issued":["2010"],"dc:description":["Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2010.","Cataloged from PDF version of thesis.","Includes bibliographical references (p. 191-209)."],"dc:description.abstract":["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."],"dc:description.degree":["Ph.D."],"dc:identifier.uri":["http://hdl.handle.net/1721.1/60786"],"dc:language.iso":["eng"],"dc:publisher":["Massachusetts Institute of Technology"],"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."],"dc:rights.uri":["http://dspace.mit.edu/handle/1721.1/7582"],"dc:subject":["Biological Engineering."],"dc:title":["Cytokine signaling control of naïve CD8⁺ T-cell homeostasis"],"dc:type":["Thesis"]},"updated_at":"2026-07-22T22:21:41Z"}