CD3 Ligation on Immature Thymocytes Generates Antagonist-like Signals Appropriate for CD8 Lineage Commitment, Independently of T Cell Receptor Specificity

The signals that direct differentiation of T cells to the CD4 or CD8 lineages in the thymus remain poorly understood. Although it has been relatively easy to direct differentiation of CD4 single positive (CD4⁺) cells using combinations of antibodies and pharmacological agents that mimic receptor engagements, equivalent stimuli do not induce efficient maturation of CD8⁺ cells. Here we report that, irrespective of the MHC-restriction specificity of the TCR, differentiation of mature CD8⁺ thymocytes can be induced by ligation of CD3 polypeptides on immature thymocytes with a F(ab′)₂ reagent (CD3fos-F(ab′)₂). The tyrosine phosphorylation patterns stimulated by CD3fos-F(ab′)₂ have been shown to resemble those delivered to mature T cells by antagonist peptides, which are known to direct positive selection of CD8⁺ cells, and we can show that this reagent exhibits potent antagonistic-like activity for primary T cell responses. Our results suggest a distinction in the signals that specify lineage commitment in the thymus. We present a model of thymocyte differentiation that proposes that the relative balance of signals delivered by TCR engagement and by p56^lck activation is responsible for directing commitment to the CD8 or CD4 lineages.