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Donor CD8⁺ T Cells Mediate Graft-versus-Leukemia Activity without Clinical Signs of Graft-versus-Host Disease in Recipients Conditioned with Anti-CD3 Monoclonal Antibody¹

Chunyan Zhang^2,*, Jingwei Lou^2,*, Nainong Li^*,, Ivan Todorov^*, Chia-Lei Lin^*, Yu-An Cao, Christopher H. Contag, Fouad Kandeel^*, Stephen Forman^* and Defu Zeng^3,*

^* Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010; Stanford University School of Medicine, Stanford, CA 94305; and Fujian Medical University Union Hospital, Fuzhou, Fujian, P. R. China

Donor CD8⁺ T cells play a critical role in mediating graft-vs-leukemia (GVL) activity, but also induce graft-vs-host disease (GVHD) in recipients conditioned with total body irradiation (TBI). In this study, we report that injections of donor C57BL/6 (H-2^b) or FVB/N (H-2^q) CD8⁺ T with bone marrow cells induced chimerism and eliminated BCL1 leukemia/lymphoma cells without clinical signs of GVHD in anti-CD3-conditioned BALB/c (H-2^d) recipients, but induced lethal GVHD in TBI-conditioned recipients. Using in vivo and ex vivo bioluminescent imaging, we observed that donor CD8⁺ T cells expanded rapidly and infiltrated GVHD target tissues in TBI-conditioned recipients, but donor CD8⁺ T cell expansion in anti-CD3-conditioned recipients was confined to lymphohematological tissues. This confinement was associated with lack of up-regulated expression of ₄₇ integrin and chemokine receptors (i.e., CXCR3) on donor CD8⁺ T cells. In addition, donor CD8⁺ T cells in anti-CD3-conditioned recipients were rendered unresponsive, anergic, Foxp3⁺, or type II cytotoxic T phenotype. Those donor CD8⁺ T cells showed strong suppressive activity in vitro and mediated GVL activity without clinical signs of GVHD in TBI-conditioned secondary recipients. These results indicate that anti-CD3 conditioning separates GVL activity from GVHD via confining donor CD8⁺ T cell expansion to host lymphohemological tissues as well as tolerizing them in the host.

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 (NIH) Grant R21-DK71002 (to D.Z.), a pilot grant from Lymphoma Special Program Grant of Research Excellence (to S.F.), NIH Grant KO1-DK071716 (to Y.-A.C.), and NIH Grant R24-CA92862 (to C.H.C.).

² C.Z. and J.L. contributed equally.

³ Address correspondence and reprint requests to Dr. Defu Zeng, Beckman Research Institute, City of Hope National Medical Center, Gonda Building, R2017, 1500 East Duarte Road, Duarte, CA 91010. E-mail address: dzeng{at}coh.org

⁴ Abbreviations used in this paper: HCT, hemopoietic cell transplantation; GVHD, graft-vs-host disease; TBI, total body irradiation; Tc, cytotoxic T; LN, lymph node; GALT, gut-associated lymphoid tissue; CLA, cutaneous lymphocyte Ag; GVL, graft vs leukemia; BLI, bioluminescent imaging; TCD, T cell depleted; BM, bone marrow.

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