TCR-Independent Activation of Extrathymically Developed, Self Antigen-Specific T Cells by IL-2/IL-15

Abstract

Naive intrathymically developed T cells, which express foreign Ag-specific TCR, do not express IL-2R. After antigenic stimulation, they express high affinity IL-2R, which enables IL-2 to be used as an autocrine growth factor. On the contrary, extrathymically developed T cells, which express self Ag-specific TCR but are unresponsive to antigenic stimulation, spontaneously express low affinity IL-2R. In this study, we compared the responses of these two subsets of T cells to IL-2R stimulation and examined the influences of TCR-mediated signaling on the responses. IL-2 or IL-15 augmented the proliferative response of Ag-stimulated, intrathymically developed T cells. On the other hand, extrathymically developed T cells proliferated in response to IL-2 or IL-15, independently of Ag stimulation. Furthermore, both IL-2 and IL-15 induced IFN-γ production of these T cells, which is strikingly augmented by the presence of IL-12. These results revealed functional differences between intrathymically developed, foreign Ag-specific T cells and extrathymically developed, self Ag-specific T cells. The latter can be activated by some inflammatory cytokines, in an Ag-independent manner, similar to NK cells.

Self-Antigen Maintains the Innate Antibacterial Function of Self-Specific CD8 T Cells In Vivo

“…Previous studies had shown that the expansion of self-specific CD8 T cells in response to either IL-2 or IL-15 in vitro was independent of self-Ag interactions (32). Our studies have suggested that self-Ag interactions played a role in the proliferation of self-specific CD8 T cells in vivo during LM infection (26).…”

“…Previous reports have shown that self-specific CD8 T cells can proliferate and become activated in vitro in response to IL-2 or IL-15 (32). The expression of IL-2R␤ (CD122) in conjunction with common ␥ chain (CD132) is sufficient to confer lymphocytes with the ability to respond to both IL-2 and IL-15 (33,34).…”

Thymus-Dependent Memory Phenotype CD8 T Cells in Naive B6.H-2Kb−/−Db−/− Animals Mediate an Antigen-Specific Response against Listeria monocytogenes

“…However, memory phenotype CD4 cells are also found in naive mice maintained under germfree conditions, suggesting that their development is not foreign Ag dependent (51). Because T cells from male anti-H-Y TCR-transgenic mice can develop extrathymically and display memory markers, it is possible that the development of memory phenotype CD8 T cells in naive mice is driven by the interaction of the ␣␤TCR with self-Ags and developed extrathymically (13,18,19). However, our finding that only a small percentage of CD8␣␤ cells develop in Txbm DKO mice compared with thymusintact bm chimeras suggests that most non-class Ia-selected CD8␣␤ cells are from the thymus-dependent pathway.…”

“…IL-2-activated CD8CD44 high cells are able to kill syngeneic tumor cells, suggesting that they may play a role in the surveillance of host cells that have been altered through infection or transformation (17). By analogy with H-Y Ag-specific TCR-transgenic mice, it has been suggested that the development of a significant portion of memory phenotype CD8 T cells in naive wild-type mice is driven by the interaction of ␣␤TCR with self-Ags and occurs extrathymically (13,18,19 (20). In the thymus of DKO mice, most mature single-positive CD8␣␤ T cells are CD44 low , similar to those in B6 mice (21).…”

Self-reactive memory-phenotype CD8 T cells exhibit both MHC-restricted and non-MHC-restricted cytotoxicity: a role for the T-cell receptor and natural killer cell receptors

“…Another unusual feature of these CD8 lo T cells is that they proliferate in response to cytokines such as IL-2 and IL-15 in an antigen-independent manner. 9 However, the CD8 lo cells are similar to conventional memory T cells with regard to the ability to rapidly produce interferon ␥ (IFN-␥) upon TCR stimulation 10 and in respect to the killing of susceptible target cells without the need for additional reactivation with antigen. 11,12 CD8 ϩ T cells that develop via an extrathymic pathway and possessing similar functional characteristics are also found in normal (non-TCR transgenic) mice.…”