CD8+ Central Memory T Cells Mediate Graft-Versus-Host Disease Although Retain Graft-Versus-Leukemia Effect.
Authors: Zheng Hong , Matte Catherine C. , Anderson Britt E. , Venkatesan Srividhya , Jain Dhanpat , Shlomchik Mark J. , Shlomchik Warren D. 
Published: April 2020

Abstract
Whereas effector memory (EM) T cells (CD62LloCCR7neg) quickly express effector functions upon restimulation and preferentially migrate to tissues and spleen, central memory (CM) T cells (CD62LhiCCR7pos) have hybrid properties of both naïve (N) and effector cells. Like N cells, their adhesion and chemokine receptors promote migration to LNs; however, their effector functions are more vigorous than N cells, yet slower than EM cells. We and others have demonstrated that EM CD4 and CD8 cells do not cause GVHD. We have also shown that EM CD4 cells can transfer immunity to a model antigen and can mediate GVL against a murine model of CML. However, much less is known about the GVHD and GVL-inducing potential of CD8 CM cells. To address this we first determined whether sorted CD8 CM cells mediate GVHD in a MHC matched (C3H.SW→B6; both H-2b) and a MHC-mismatched (B6 (H-2b) →BALB/c (H-2d)) GVHD model. In the C3H.SW→B6 model, lethally irradiated recipients were given donor BM with no T cells or with 1.5X106 CD8+CD62L+CD44- naïve (N) or CD8+CD62L+CD44+ central memory (CM) donor T cells. Group sizes were small in this initial experiment. N cell recipients (n=7) had significantly more weight loss than BM alone recipients (n=5). However, with regard to weight loss, CM recipients (n=4) were not statistically different from either BM alone or N cell recipients, though a trend suggested that CM recipients had less weight loss than N recipients. Nonetheless, there was clear histologic evidence of hepatic and small bowel GVHD in recipients of CD8 CM cells which was similar to that seen in naïve CD8 recipients. In the B6→BALB/c model, as expected N cells induced significantly more weight loss than BM alone. CM cell recipients had significantly more weight loss than BM alone recipients only at early time points and had less weight loss than N cells recipients at most time points. In this experimental system liver GVHD is the dominant histologic finding. Clear hepatic GVHD with marked periportal inflammatory infiltration was present in CM cell recipients, qualitatively similar to that seen in recipients of N cells. Thus, although we observed differences in weight loss, CM cells nevertheless caused histologic GVHD in both MHC-matched and MHC-disparate transplant models. We also compared the efficacy of N and CM CD8 cells in mediating GVL against a model of CML created via retroviral transduction of the bcr-abl fusion cDNA (p210) into BM cells. BALB/c recipients were lethally irradiated and reconstituted with B6 BM, B6 BM infected with a bcr-abl expressing retrovirus that also expresses NGFR along with no T cells or with 1X106 N or CM CD8 cells. All recipients of CML without CD8 cells died by day 16. In contrast 7/7 recipients of CM CD8 cells survived to the end of the experiment at day+48 (P=0.0007). 3/7 recipients of naïve cells died of leukemia by day 16; the remainder survived until the end of the experiment. All surviving mice had histologic GVHD but no evidence of CML in spleen, BM and peripheral blood as measured by FACS. These experiments demonstrate that CM CD8 cells cause a milder but definite form of GVHD in MHC-disparate and MHC-matched models while at the same time they mediate effective GVL. Nevertheless, strategies aiming to use M T cells for reconstitution of immunity and GVL post transplant will likely need to exclude CD8 CM cells.