The Journal of Immunology, Vol 159, Issue 2 606-613, Copyright © 1997 by American Association of Immunologists

ARTICLES

Cytokine-deficient CD8+ Tc1 cells induced by IL-4: retained inflammation and perforin and Fas cytotoxicity but compromised long term killing of tumor cells

S Sad, L Li and TR Mosmann
Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Canada. Subash.Sad@nrc.ca

After antigenic stimulation, naive CD8+ T cells differentiate into cytotoxic Tc1 cells secreting the cytokines IL-2, IFN-gamma, and TNF, which aid their proliferation and effector functions. We have previously shown that IL-4 acts directly on differentiated Tc1 cells to impair subsequent Con A-induced IL-2 production. As IL-4 may be produced in the vicinity of Tc1 cells during normal immune responses, we have further analyzed the short and long term functions of IL-4- treated Tc1 cells. We now show that these cells also have a defect in the synthesis of IFN-gamma, TNF, and IL-10 in response to antigenic stimulation. IL-2 synthesis was the most sensitive, as stimulation of IL-4-treated Tc1 cells with higher numbers of APCs partially restored IFN-gamma, TNF, and IL-10, but not IL-2, synthesis. Injection of allo- specific Tc1 cells into mice expressing the target Ag revealed reduced cytokine synthesis in vivo by IL-4-treated Tc1 cells. Loss of cytokine synthesis did not impair the short term effector functions of Tc1 cells, as they induced adoptively transferred delayed type hypersensitivity in recipient mice and retained both perforin- and Fas- dependent cytolytic mechanisms in vitro. Long term coculture of tumor targets and tumor-specific Tc1 cells indicated that normal Tc1 cells proliferated and killed tumor cells, whereas IL-4-treated Tc1 cells failed to proliferate and hence were unable to curtail the proliferation of tumor cells. These results suggest that IL-4 synthesis in vivo would not affect immediate effector functions of differentiated Tc1 cells, but would compromise immunity by reducing their long term functional capability.

This article has been cited by other articles:

				Y.-J. Kim, T. M. Stringfield, Y. Chen, and H. E. Broxmeyer Modulation of cord blood CD8+ T-cell effector differentiation by TGF-{beta}1 and 4-1BB costimulation Blood, January 1, 2005; 105(1): 274 - 281. [Abstract] [Full Text] [PDF]

				J. J. Sussman, R. Parihar, K. Winstead, and F. D. Finkelman Prolonged Culture of Vaccine-Primed Lymphocytes Results in Decreased Antitumor Killing and Change in Cytokine Secretion Cancer Res., December 15, 2004; 64(24): 9124 - 9130. [Abstract] [Full Text] [PDF]

				R. J. Jackson, A. J. Ramsay, C. D. Christensen, S. Beaton, D. F. Hall, and I. A. Ramshaw Expression of Mouse Interleukin-4 by a Recombinant Ectromelia Virus Suppresses Cytolytic Lymphocyte Responses and Overcomes Genetic Resistance to Mousepox J. Virol., February 1, 2001; 75(3): 1205 - 1210. [Abstract] [Full Text]

				C. Vizler, N. Bercovici, A. Heurtier, N. Pardigon, K. Goude, K. Bailly, C. Combadiere, and R. S. Liblau Relative Diabetogenic Properties of Islet-Specific Tc1 and Tc2 Cells in Immunocompetent Hosts J. Immunol., December 1, 2000; 165(11): 6314 - 6321. [Abstract] [Full Text] [PDF]

				A. S. Diamond and R. G. Gill An Essential Contribution by IFN-{gamma} to CD8+ T Cell-Mediated Rejection of Pancreatic Islet Allografts J. Immunol., July 1, 2000; 165(1): 247 - 255. [Abstract] [Full Text] [PDF]

				A. Ribas, L. H. Butterfield, B. Hu, V. B. Dissette, W. S. Meng, A. Koh, K. J. Andrews, M. Lee, S. N. Amar, J. A. Glaspy, et al. Immune Deviation and Fas-mediated Deletion Limit Antitumor Activity after Multiple Dendritic Cell Vaccinations in Mice Cancer Res., April 1, 2000; 60(8): 2218 - 2224. [Abstract] [Full Text]

				T. Y. Shibuya, W.-Z. Wei, M. Zormeier, J. Ensley, W. Sakr, R. H. Mathog, R. J. Meleca, G. H. Yoo, C. H. June, B. L. Levine, et al. Anti-CD3/Anti-CD28 Bead Stimulation Overcomes CD3 Unresponsiveness in Patients With Head and Neck Squamous Cell Carcinoma Arch Otolaryngol Head Neck Surg, April 1, 2000; 126(4): 473 - 479. [Abstract] [Full Text] [PDF]

				M. Vukmanovic-Stejic, B. Vyas, P. Gorak-Stolinska, A. Noble, and D. M. Kemeny Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distinct cell surface and functional phenotypes Blood, January 1, 2000; 95(1): 231 - 240. [Abstract] [Full Text] [PDF]

				G. E. Peoples, B. W. Anderson, T. V. Lee, J. L. Murray, A. P. Kudelka, J. T. Wharton, and C. G. Ioannides Vaccine Implications of Folate Binding Protein, a Novel Cytotoxic T Lymphocyte-recognized Antigen System in Epithelial Cancers Clin. Cancer Res., December 1, 1999; 5(12): 4214 - 4223. [Abstract] [Full Text] [PDF]

				S. Sad and L. Krishnan Cytokine Deprivation of Naive CD8+ T Cells Promotes Minimal Cell Cycling but Maximal Cytokine Synthesis and Autonomous Proliferation Subsequently: A Mechanism of Self-Regulation J. Immunol., September 1, 1999; 163(5): 2443 - 2451. [Abstract] [Full Text] [PDF]

				C. A. Gullo, M. T. Esser, C. L. Fuller, and V. L. Braciale Generation of IL-2-Dependent Cytolytic T Lymphocytes (CTLs) with Altered TCR Responses Derived from Antigen-Dependent CTL Clones J. Immunol., June 1, 1999; 162(11): 6466 - 6472. [Abstract] [Full Text] [PDF]

				M. C. Villacres and C. C. Bergmann Enhanced Cytotoxic T Cell Activity in IL-4-Deficient Mice J. Immunol., March 1, 1999; 162(5): 2663 - 2670. [Abstract] [Full Text] [PDF]