Abstract

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. A small increase in the strength of the pMHCI/CD8 interaction (~1.5-fold) can disproportionately amplify this effect, boosting antigen sensitivity by up to two orders of magnitude. However, recognition specificity is lost altogether with more substantial increases in pMHCI/CD8 affinity (~10-fold). In this study, we used a panel of MHCI mutants with altered CD8-binding properties to show that TCR-mediated antigen specificity is delimited by a pMHCI/CD8 affinity threshold. Our findings suggest that CD8 can be engineered within certain biophysical parameters to enhance the therapeutic efficacy of adoptive T-cell transfer irrespective of antigen specificity.

Highlights

  • The CD8 co-receptor engages peptide-major histocompatibility complex class I molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity

  • Some variation exists between different major histocompatibility complex class I (MHCI) molecules due to polymorphisms that affect the CD8 binding site, the average peptide-major histocompatibility complex class I (pMHCI)/CD8 interaction occurs with an equilibrium dissociation constant (KD) ~ 145 μM.[25,32]

  • Weaker pMHCI/CD8 solution binding affinities have been reported for human leukocyte antigen (HLA) A*6801, HLA B*4801 and HLA B*8101.22,25 The introduction of a glutamine (Q) to glutamic acid (E) substitution at position 115 of the MHCI α2 domain increases the pMHCI/CD8 interaction by ~ 1.5-fold (KD ~ 98 μM) without impacting the TCR/pMHCI binding platform.[26]

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Summary

Introduction

The CD8 co-receptor engages peptide-major histocompatibility complex class I (pMHCI) molecules at a largely invariant site distinct from the T-cell receptor (TCR)-binding platform and enhances the sensitivity of antigen-driven activation to promote effective CD8+ T-cell immunity. One key limitation relates to the naturally low affinity of self-derived antigen-specific TCRs,[8,9] which constrains the functional properties of tumour-associated antigen-specific CD8+ T-cell populations This intrinsic problem stems from the negative selection of high-affinity autoreactive αβ TCR clonotypes during thymic education and most likely explains why it has proven difficult to develop cancer vaccines in the absence of a clear oncogenic microbial agent. It is notable in this regard that pMHCI/CD8 binding is characterized by very low solution affinities (average KD ~ 145 μM).[25] an incremental increase in the strength of this interaction (KD ~ 98 μM) can boost antigen sensitivity by up to 100-fold.[17,26] Such manipulations are globally applicable across TCR specificities due to the nonpolymorphic nature of CD8, thereby providing a generic opportunity to enhance CD8+ T-cell reactivity for therapeutic purposes.[27] substantial increases in pMHCI/CD8 affinity can abrogate antigen specificity.[28]. The pMHCI/CD8 interaction controls T-cell specificity T Dockree et al guidelines for the rational design of high-affinity CD8 molecules to optimize the therapeutic efficacy of adoptive T-cell transfer

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