Multifaceted role of BTLA in the control of CD8+ T cell fate after antigen encounter

Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40-50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte attenuator) expression on transferred CD8⁺ TIL was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8⁺BTLA⁺TIL subset and define the contribution of the Grb2 motif of BTLA in T cell co-stimulation. <br /><br />Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8⁺ TIL and mouse CD8⁺ T cells. Functional assays were used including single cell analysis, Reverse Phase Protein Array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as Patient-Derived Xenograft (PDX) model using Immunodeficient NOD-scid IL2Rgamma^null (NSG) tumor-bearing mice treated with autologous TIL.<br /> <p>Results: CD8⁺BTLA^- TIL could not control tumor growth in vivo as well as their BTLA⁺ counterpart and antigen-specific CD8⁺BTLA^- T cells had impaired recall response to a vaccine. However CD8⁺BTLA⁺ TIL displayed improved survival following the killing of a tumor target and heightened "serial killing" capacity. Using mutants of BTLA signaling motifs we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation. <br /><br />Conclusions:Our data portrays BTLA as a molecule with the singular ability to provide both co-stimulatory and co-inhibitory signals to activated CD8⁺ T cells, resulting in extended survival, improved tumor control and the development of a functional recall response.

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