An active CD8α/pMHCI interaction is required for CD8 single positive thymocyte differentiation

Recognition of viral antigenic peptides bound to major histocompatibility complex class I molecules (MHCI) by TCR is critical for initiating the responses of CD8⁺ T cells that ultimately lead to elimination of virus-infected cells. This antigen recognition is enhanced by the CD8 coreceptor through its interaction with the peptide-MHCI complexes (pMHCI). Mouse CD8αβ can form two different complexes with pMHCI via either the CD8α- or CD8β-dominated interaction. To understand the functional significance of these complexes in vivo, we generated Tg mice carrying a variant CD8αβ (CD8α^m3β) capable of forming only the CD8β-dominated CD8αβ/pMHCI complex. These mice show sub-optimal thymic differentiation with reduced populations of CD8⁺ single-positive thymocytes. Tg CD8⁺ T cells exhibit a compromised developmental capacity when competing with CD8⁺ T cells from B6 mice in mixed bone marrow chimera experiments. However, once these CD8⁺ T cells have emigrated to the peripheral lymphoid organs, they exhibit normal effector function against viral infection. Our observations indicate that, in addition to the CD8 activity conferred by CD8β-dominated CD8αβ/pMHCI complexes, full thymocyte differentiation requires additional coreceptor activities conferred by CD8αα and/or CD8αβ with CD8α-dominated CD8/pMHCI complexes.