Proliferation and differentiation of CD8+ T cells in the absence of IL-2/15 receptor beta-chain expression or STAT5 activation.
Major gains in the efficacy of T cell-based therapies for cancer and infectious diseases could be realized through improved understanding of the signals that control expansion and differentiation of CD8(+) cytolytic T cells. IL-2, IL-15, and the downstream transcription factor STAT5 have all been implicated as important regulators of these processes, yet there are conflicting data regarding their contribution to in vivo T cell responses. We used a murine adoptive T cell transfer model to examine the contribution of IL-2 and IL-15 signaling to the proliferation and differentiation of naive, CD8(+) T cells bearing an OVA-specific TCR transgene (OT-I). OT-I T cells failed to express the high affinity IL-2R (CD25) while proliferating in vivo, irrespective of the mode of Ag delivery. Moreover, OT-I T cells rendered genetically deficient in the shared IL-2/IL-15Rbeta subunit (IL-2Rbeta) demonstrated normal Ag-induced proliferation and cytolytic activity in vivo. Accordingly, activation of STAT5 was not detected in proliferating IL-2Rbeta-deficient OT-I T cells, thus implicating a STAT5-independent cytokine or costimulatory pathway in this process. Even though IL-2 and IL-15 were dispensable for CD8(+) T cell proliferation, systemic infusion of IL-2 nevertheless promoted the expansion of OT-I T cells in vivo. Thus, IL-2 and IL-15 signals are not essential for CD8(+) T cell proliferation or differentiation, but IL-2 can promote supraphysiological expansion when supplied exogenously. These findings challenge current models that place CD8(+) T cell proliferation under the control of STAT5-dependent cytokines and suggest new approaches to the therapeutic manipulation of T cell numbers in vivo.
Benaroya Research Institute, Virginia Mason, Seattle, WA, USA.
Ryan M
RM
Teague
Richard M
RM
Tempero
Sunil
S
Thomas
Kaja
K
Murali-Krishna
Brad H
BH
Nelson
D000970:Antineoplastic Agents / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects / Q000276:immunology; D004268:DNA-Binding Proteins / Q000276:immunology*; D066298:In Vitro Techniques; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D008894:Milk Proteins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000276:immunology*; D050799:STAT5 Transcription Factor; D015534:Trans-Activators / Q000276:immunology*
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D019409:Interleukin-15; D007376:Interleukin-2; D008894:Milk Proteins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D015534:Trans-Activators