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IL-12-Independent LIGHT Signaling Enhances MHC Class II Disparate CD4⁺ T Cell Alloproliferation, IFN- Responses, and Intestinal Graft-versus-Host Disease¹

Geri R. Brown^2,*,, Edward L. Lee^,, Jihad El-Hayek^*, Katherine Kintner^* and Cheryl Luck^*

^* Division of Digestive and Liver Diseases, Department of Internal Medicine, and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and Veterans Affairs Medical Center, Dallas, TX 75216

Inhibition of LIGHT (a cellular ligand for herpes virus entry mediator and lymphotoxin receptor)/herpes simplex virus entry mediator (HVEM) and LIGHT/lymphotoxin receptor (LTR) interactions decreases mortality in MHC class I and II disparate graft-vs-host disease (GVHD). The present studies assessed the effects of these interactions on the generation of CD4⁺ T cell alloresponses in MHC class II-disparate MLC and GVHD. An inhibitor protein of LIGHT and LT2 (LTR-Ig) and an inhibitor protein of LIGHT (HVEM-Ig) caused similar decreases in alloresponses of control B6 or B6.129S1-IL12rb2^tm1Jm (B6.IL12R^–/–) spleen cells (SpC) in a MHC class II-disparate MLC. GVHD-induced wasting disease in MHC class II-disparate recipients of B6 CD4⁺ SpC who received either the LTR-Ig-encoding adenovirus (LTR-Ig Adv; 13.1 ± 10.9%; n = 10; p = 0.0004) or the HVEM-Ig-encoding adenovirus (HVEM-Ig Adv; 16.4 ± 9.9%; n = 13; p = 0.0008) was significantly reduced compared with that in recipients of a control adenovirus (30.4 ± 8.8%; n = 13). Furthermore, gut GVHD histologic scores of recipients of B6 CD4⁺ SpC who received the LTR-Ig Adv (0.8 ± 0.8; n = 5; p = 0.0007) or the HVEM-Ig Adv (1.4 ± 0.5; n = 5; p = 0.008) were reduced compared with scores of recipients of a control adenovirus (2.5 ± 0.75; n = 11). In the intestine, both LTR-Ig Adv and HVEM-Ig Adv decreased CD4⁺ T cells (0.35 ± 0.4 x 10⁶ (n = 6) vs 0.36 ± 0.02 x 10⁶ (n = 9); p = 0.03 and p = 0.007) compared with control adenovirus (0.86 ± 0.42 x 10⁶; n = 9). LIGHT is critical for optimal CD4⁺ T cell alloresponses in MHC class II-disparate MLC and GVHD.

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