A Conversation with Cohn on the Activation of <scp>CD</scp> 4 T Cells

Despite an agreement on most issues surrounding models for how lymphocytes are activated and inactivated, and arising out of the 1970 Two Signal Model of lymphocyte activation, Cohn and I have different perspectives on two critical issues concerning the activation of CD4 T cells. One issue is the origin of the first effector T helper (eTh) cells, postulated by both of us to be required to optimally activate precursor Th (pTh), that is na&#239;ve CD4 T cells, to further generate eTh cells. The second issue arises from our agreement that the antigen‐dependent CD4 T cell cooperation, that we both postulate is required to activate na&#239;ve CD4 T (pTh) cells, most likely is mediated by the operational recognition of linked epitopes. Although agreeing on the centrality of this operational mechanism, we disagree about how it might be realized at the molecular/cellular level. I respond here to issues raised by Cohn concerning these two mechanistic questions, in his response to my recent article on the activation and inactivation of mature CD4 T cells.