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.