T cell major histocompatibility complex class II molecules down‐regulate CD4+ T cell clone responses following LAG‐3 binding

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Abstract
T cell response to its antigen requires recognition by the T cell receptor together with a co‐receptor molecule, either CD4 or CD8. Additional molecules have been identified that are capable of delivering the co‐stimulatory signals provided by APC. Following T cell priming, a number of T cell activation antigens are expressed that may play a role in the inactivation phase of the T cell response. The lymphocyte activation gene (LAG)‐3 protein and its counter‐receptors, the major histocompatibility complex (MHC) class II molecules, are such activation antigens whose interaction may result in the down‐regulation of the ongoing immune response. To investigate the role of LAG‐3/class II molecule interaction, we produced a soluble form of LAG‐3 by fusing the extracellular Ig domains of this membrane protein to the constant region of human IgG1 (LAG‐31g). Here, we show a direct and specific binding of LAG‐3Ig to class II molecules on the cell surface. In addition, we show that LAG‐3/class II molecule interaction leads to the down‐regulation of CD4+ Ag‐specific T cell clone proliferation and cytokine secretion. This inhibitory effect is observed at the level of the effector cells and not the APC and is also found with anti‐CD3 mAb, PHA + PMA or low‐dose IL‐2 driven stimulation in the absence of APC. These functional studies indicate that T cell MHC class II molecules down‐regulate T cell proliferation following LAG‐3 binding and suggest a role for LAG‐3 in the control of the CD4+ T cell response.