Cytokine-Independent Proliferation of IL-2-Nonproducing CTL Clones in Association with High TCR-Signal Transduction Responses

Fumihiko Nagase; Tint Lwin; Izumi Nakashima

Fumihiko Nagase, Tint Lwin, Izumi Nakashima

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Keywords: IL-2-nonproducing CTL clones, Cytokine-independent proliferation, Signal transduction

JOURNAL FREE ACCESS

1996 Volume 40 Issue 7 Pages 505-511

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Published: July 20, 1996 Received: February 05, 1996 Available on J-STAGE: March 17, 2008 Accepted: April 18, 1996 Advance online publication: - Revised: -
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Date of correction: March 17, 2008 Reason for correction: - Correction: ABSTRACT Details: Wrong : Alloreactive CTL clone D2-23 proliferated in response to antigenic cells without IL-2 production. Among subclones of D2-23, the F1 but not F2 clone proliferated in response to soluble aCD3 or PMA, although both clones proliferated in response to immobilized aCD3, antigenic cells or soluble aCD3 plus costimulatory cells. The difference in responsiveness between F1 and F2 was not caused by distinct expression of CD3 or Fc receptors. Cyclosporin A, which totally blocks IL-2 production of Th1 cells, barely or only partially inhibited PMA- or aCD3-induced proliferation of F1. F1 did not produce cytokines for proliferation of F2 in response to soluble aCD3. Tyrosine phosphorylation developed for various proteins of F1 and F2 at the levels apparently correlated to the extent of cell proliferation when the cells were stimulated with soluble aCD3 or PMA. The proliferative responsiveness of F1 and F2 to the described stimulators was maintained by stimulation with IL-2 plus antigenic cells, or even IL-2 alone, but was decreased during resting culture or by stimulation with immobilized aCD3. These results show evidence of a new TCR-linked mechanism for CTL proliferation that is independent of costimulatory cell- or cytokine-mediated signaling, but is originally prepared by prior stimulation with IL-2.
Right : Alloreactive CTL clone D2-23 proliferated in response to antigenic cells without IL-2 production. Among subclones of D2-23, the Fl but not F2 clone proliferated in response to soluble aCD3 or PMA, although both clones proliferated in response to immobilized aCD3, antigenic cells or soluble aCD3 plus costimulatory cells. The difference in responsiveness between F1 and F2 was not caused by distinct expression of CD3 or Fc receptors. Cyclosporin A, which totally blocks IL-2 production of Th1 cells, barely or only partially inhibited PMA-or aCD3-induced proliferation of F1. F1 did not produce cytokines for proliferation of F2 in response to soluble aCD3. Tyrosine phosphorylation developed for various proteins of F1 and F2 at the levels apparently correlated to the extent of cell proliferation when the cells were stimulated with soluble aCD3 or PMA. The proliferative responsiveness of F1 and F2 to the described stimulators was maintained by stimulation with IL-2 plus antigenic cells, or even IL-2 alone, but was decreased during resting culture or by stimulation with immobilized aCD3. These results show evidence of a new TCR-linked mechanism for CTL proliferation that is independent of costimulatory cell-or cytokine-mediated signaling, but is originally prepared by prior stimulation with IL-2.

Date of correction: March 17, 2008 Reason for correction: - Correction: DTPUB Details: Right : 19960720

Date of correction: March 17, 2008 Reason for correction: - Correction: CITATION Details: Wrong : 1) Beverly, B., Kang, S.-M., Lenardo, M.J., and Schwartz, R.H. 1992. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int. Immunol. 4: 661-671.
2) Desilva, D.R., Urdahl, K.B., and Jenkins, M.K. 1991. Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation. J. Immunol. 147: 3261-3267.
3) Gilbert, K.M., Hoang, K.D., and Weigle, W.O. 1990. Th1 and Th2 clones differ in their response to a tolerogenic signal. J. Immunol. 144: 2063-2071.
4) Jenkins, M.K., Chen, C., Jung, G., Mueller, D.L., and Schwartz, R.H. 1990. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J. Immunol. 144: 16-22.
5) June, C.H., Bluestone, J.A., Nadler, L.M., and Thompson, C.B. 1994. The B7 and CD28 receptor families. Immunol. Today 15: 321-332.
6) Kim, D.-K, Otten, G., Moldwin, R.L., Dunn, D.E., Nau, G.J., and Fitch, F.W. 1986. PMA alone induces proliferation of some T cell clones but not others. J. Immunol. 137: 2755-2760.
7) Leo, O., Foo, M., Sachs, D.H., Samelson, L.E., and Bluestone, J.A. 1987. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc. Natl. Acad. Sci. U.S.A. 84: 1374-1378.
8) Lwin, T., Nakashima, I., and Nagase, F. 1995. TCR-independent induction of low responsiveness by chemically fixed cells in alloreactive CTL clones and its prevention through cognate cell-cell interaction. Microbiol. Immunol. 39: 509-515.
9) Lwin, T., Nakashima, I., and Nagase, F. 1995. Down-regulation of T-cell proliferation in response to soluble anti-CD3 antibodies through development of redirected cytolytic activity eliminating costimulatory cells. Microbiol. Immunol. 39: 599-606.
10) Moldwin, R.L., Lanki, D.W., Herold, K.C., and Fitch, F.W. 1986. An antigen receptor-driven, interleukin 2-independent pathway for proliferation of murine cytolytic T lymphocyte clones. J. Exp. Med. 163: 1566-1582.
11) Mueller, D.L., Jenkins, M.K., and Schwartz, R.H. 1989. Clonal expansion versus functional clonal inactivation: a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu. Rev. Immunol. 7: 445-480.
12) Nakashima, I., Pu, M., Nishizaki, A., Rosila, I., Ma, L., Katano, Y., Ohkusu, K., Rahman, S.M.J., Isobe, K., Hamaguchi, M., and Saga, K. 1994. Redox mechanism as alternative to ligand binding for receptor activation delivering disregulated cellular signals. J. Immunol. 152: 1064-1071.
13) Otten, G.R., and Jermain, R.N. 1991. Split anergy in a CD8⁺ T cell: receptor-dependent cytolysis in the absence of interleukin-2 production. Science 251: 1228-1231.
14) Pastor, M.I., Reif, K., and Cantrell, D. 1995. The regulation and function of p21^ras during T-cell activation and growth. Immunol. Today 16: 159-164.
15) Williams, I.R., and Unanue, E.R. 1990. Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody. J. Immunol. 145: 85-93.
16) Williams, M.E., Shea, C.M., Lichtman, A.H., and Abbas, A.K. 1992. Antigen receptor-mediated anergy in resting T lymphocytes and T cell clones. Correlation with lymphokine secretion patterns. J. Immunol. 149: 1921-1926.

Right : 1) Beverly, B., Kang, S.-M., Lenardo, M.J., and Schwartz, R.H. 1992. Reversal of in vitro T cell clonal anergy by IL-2 stimulation. Int. Immunol. 4 : 661-671.
2) Desilva, D.R., Urdahl, K.B., and Jenkins, M.K. 1991. Clonal anergy is induced in vitro by T cell receptor occupancy in the absence of proliferation. J. Immunol. 147 : 3261-3267.
3) Gilbert, KM., Hoang, K.D., and Weigle, W.O. 1990. Thl and Th2 clones differ in their response to a tolerogenic signal. J. Immunol. 144 : 2063-2071.
4) Jenkins, M.K., Chen, C., Jung, G., Mueller, D.L., and Schwartz, R.H. 1990. Inhibition of antigen-specific proliferation of type 1 murine T cell clones after stimulation with immobilized anti-CD3 monoclonal antibody. J. Immunol. 144 : 16-22.
5) June, C.H., Bluestone, J.A., Nadler, L.M., and Thompson, C.B. 1994. The B7 and CD28 receptor families. Immunol. Today 15 : 321-332.
6) Kim, D.-K., Often, G., Moldwin, R.L., Dunn, D.E., Nau, G.J., and Fitch, F.W. 1986. PMA alone induces proliferation of some T cell clones but not others. J. Immunol. 137 : 2755-2760.
7) Leo, O., Foo, M., Sachs, D.H., Samelson, L.E., and Bluestone, J.A. 1987. Identification of a monoclonal antibody specific for a murine T3 polypeptide. Proc. Natl. Acad. Sci. U.S.A. 84 : 1374-1378.
8) Lwin, T., Nakashima, I., and Nagase, F. 1995. TCR-independent induction of low responsiveness by chemically fixed cells in alloreactive CTL clones and its prevention through cognate cell-cell interaction. Microbiol. Immunol. 39 : 509-515.
9) Lwin, T., Nakashima, I., and Nagase, F. 1995. Down-regulation of T-cell proliferation in response to soluble anti CD3 antibodies through development of redirected cytolytic activity eliminating costimulatory cells. Microbiol. Immunol. 39 : 599-606.
10) Moldwin, R.L., Lanki, D.W., Herold, K.C., and Fitch, F.W. 1986. An antigen receptor-driven, interleukin 2-independent pathway for proliferation of murine cytolytic T lymphocyte clones. J. Exp. Med. 163 : 1566-1582.
11) Mueller, D.L., Jenkins, M.K., and Schwartz, R.H. 1989. Clonal expansion versus functional clonal inactivation : a costimulatory signalling pathway determines the outcome of T cell antigen receptor occupancy. Annu. Rev. Immunol. 7 : 445-480.
12) Nakashima, I., Pu, M., Nishizaki, A., Rosila, I., Ma, L., Katano, Y., Ohkusu, K., Rahman, S.M.J., Isobe, K., Hamaguchi, M., and Saga, K. 1994. Redox mechanism as alternative to ligand binding for receptor activation delivering disregulated cellular signals. J. Immunol. 152 : 1064-1071.
13) Otten, G.R., and Jermain, R.N. 1991. Split anergy in a CD8⁺ T cell : receptor-dependent cytolysis in the absence of inter leukin-2 production. Science 251 : 1228-1231.
14) Pastor, M.I., Reif, K., and Cantrell, D. 1995. The regulation and function of p21^ras during T-cell activation and growth. Immunol. Today 16 : 159-164.
15) Williams, I.R., and Unanue, E.R. 1990. Costimulatory requirements of murine Th1 clones. The role of accessory cell-derived signals in responses to anti-CD3 antibody. J. Immunol. 145 : 85-93.
16) Williams, M.E., Shea, C.M., Lichtman, A.H., and Abbas, A.K. 1992. Antigen receptor-mediated anergy in resting T lymphocytes and T cell clones. Correlation with lymphokine secretion patterns. J. Immunol. 149 : 1921-1926.

Abstract

Alloreactive CTL clone D2-23 proliferated in response to antigenic cells without IL-2 production. Among subclones of D2-23, the Fl but not F2 clone proliferated in response to soluble aCD3 or PMA, although both clones proliferated in response to immobilized aCD3, antigenic cells or soluble aCD3 plus costimulatory cells. The difference in responsiveness between F1 and F2 was not caused by distinct expression of CD3 or Fc receptors. Cyclosporin A, which totally blocks IL-2 production of Th1 cells, barely or only partially inhibited PMA-or aCD3-induced proliferation of F1. F1 did not produce cytokines for proliferation of F2 in response to soluble aCD3. Tyrosine phosphorylation developed for various proteins of F1 and F2 at the levels apparently correlated to the extent of cell proliferation when the cells were stimulated with soluble aCD3 or PMA. The proliferative responsiveness of F1 and F2 to the described stimulators was maintained by stimulation with IL-2 plus antigenic cells, or even IL-2 alone, but was decreased during resting culture or by stimulation with immobilized aCD3. These results show evidence of a new TCR-linked mechanism for CTL proliferation that is independent of costimulatory cell-or cytokine-mediated signaling, but is originally prepared by prior stimulation with IL-2.

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