T cells in mice expressing a transgenic human TCR beta chain get positively selected but cannot be activated in the periphery by signaling through TCR

TCR-CD3 complex-mediated signaling is crucial for both developmental select ion and antigenic activation of T cells. We report that mice expressing a r ecombined human TCR beta chain (Tg), which have normal development of T cel ls, mounted very weak responses to immunization with protein antigens as we ll as the HA307-319 peptide recognized by the human T cell clone HA1.7 from which the transgene is derived. An anti-CD3 epsilon mAb triggered equivale nt proliferation from Tg and non-Tg T cells, but an anti-human TCR beta mAb induced proliferation poorly in Tg T cells in contrast to human T cells or HA1.7. In Tg mice, T cells expressing endogenous TCR were CD44(high), wher eas most transgene-expressing T cells remained CD44(low), suggesting that t ransgene-expressing cells are not activated in the periphery to participate in immune responses. However, anti-human TCR beta could induce some activa tion markers on T cells and cross-linking of the Tg TCR by plate-coated ant i-human TCR beta efficiently induced T cell proliferation. Human TCR beta - mediated Tg T cell activation could be rescued by exogenous IL-2, as well a s by the calcium ionophore A23187, but not by phorbol esters. Thus, this hu man TCR beta chain functions efficiently for positive selection of mouse T cells, but not for their peripheral activation, probably because of a lack of oligomerization leading to defects in signaling for calcium flux and IL- 2 induction. The data thus suggest an early point of separation of signalin g pathways between positive selection and peripheral activation of T cells.