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Defective Alloreactive CD8 T Cell Function and Memory Response in Allograft Recipients in the Absence of CD4 Help¹

Yuan Zhai^*, Yue Wang^*, Zheng Wu^* and Jerzy W. Kupiec-Weglinski^2,*,

^* Division of Liver and Pancreas Transplantation, Department of Surgery, Dumont-University of California Los Angeles (UCLA) Transplant Center, and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA 90095

We have shown that alloreactive CD8 T cell activation may proceed via CD4-dependent and CD4-independent pathways, and that CD8 T cell activation in Ag-primed animals is independent of CD154 costimulation. In this report, we further analyzed the activation and function of alloreactive CD8 CTL effectors in CD4 knockout (KO) skin/cardiac allograft recipients. FACS analysis showed that alloreactive CD8 T cells were activated at a significantly reduced level in CD4 KO mice. Importantly, these helpless CD8 T cells failed to develop CD154 blockade resistance following reactivation by the same alloantigen, indicative of defective memory formation. Only transient CD4 help was required, as short-term CD4 blockade at the time of first skin graft challenge only delayed alloreactive CD8 activation, without affecting the CD8 T cell memory response to a second skin graft. Moreover, postoperative CD4 blockade had no effect on alloreactive CD8 activation. Alloreactive CD8 cells generated in the absence of CD4 help exhibited decreased effector responses. Interestingly, intragraft induction of T cell-targeted chemokines early after transplant was also dependent on CD4 help, as the induction kinetics of CXCL9 and CCL5 in CD4 KO recipients was significantly delayed, coupled with similarly delayed infiltration by CD3/CD8 cells. Remarkably, helpless CD8 cells ultimately entering the graft still displayed significantly diminished T cell effector molecules (IFN-, granzyme B). Thus, CD4 help is critical for alloreactive CD8 activation, function, and memory formation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grants AI23847, AI42223, DK62357 (to J.W.K.-W.), the American Heart Association (to Y.Z.), and the Dumont Research Foundation.

² Address correspondence and reprint requests to Dr. Jerzy W. Kupiec-Weglinski, Dumont-UCLA Transplant Center, University of California Los Angeles, Room 77-120 Center of Health Sciences, 10833 Le Conte Avenue, Los Angeles, CA 90095. E-mail address: jkupiec{at}mednet.ucla.edu

³ Abbreviations used in this paper: KO, knockout; WT, wild type; CTL_eff, CTL effector.

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