Defective CD8(+) T cell activation and cytolytic function in the absence of LPA-1 cannot be restored by increased TCR signaling

Signaling through the TCR as well as engagement of costimulatory molecules are required for efficient T cell activation and progression into different iated effector cells. The beta(2) integrin LFA-1 (CD11a/CD18) has been impl icated in TCR costimulation as well as in cell-cell adhesion function, but its exact role is still ambiguous. The present study focuses on the require ment for LFA-1 in CD8(+) T cell activation and effector function using LFA- 1-deficient cells expressing the 2C transgenic TCR as a model system. The l ack of LFA-1 expression in 2C T cells resulted in severely diminished proli ferative response toward allogeneic BALB/c splenocytes. Increase in TCR sig naling alone by pulsing stimulators with high affinity peptides, p2Ca or QL 9, had minimal effects in restoring proliferation, Addition of exogenous IL -2, however, enhanced the effect of peptide pulsing on proliferation of LFA -1-deficient 2C T cells. LFA-1-deficient 2C CTLs generated from alloantigen stimulation exhibited a defective cytotoxic activity when tested on a vari ety of target cells. Cytolysis could be improved, but not fully rectified b y peptide pulsing of target cells. Thus, in the 2C TCR model, LFA-1 has a r equisite role for optimal CD8(+) T cell activation and effector function, w hich cannot be overcome by increasing peptide/MHC density on either the APC s or target cells, respectively.