Control of CD4 Helper and CD8 Cytotoxic T cell Differentiation

Vibhuti P Dave

doi:10.33696/immunology.2.046

Abstract

Engagement of mature T cell receptor (TCR), a multiprotein complex consisting of an ?? heterodimer associated with invariant CD3 signaling proteins, on CD4+CD8+ double positive (DP) thymocytes by selfpeptide/ self-MHC complex on thymic stromal cells results in negative selection of thymocytes expressing strong affinity TCRs and positive selection of thymocytes expressing weak affinity TCRs. Positively selected thymocytes almost invariably differentiate into MHCIIspecific CD4+ helper and MHCI-specific CD8+ cytotoxic T cells endowed with effector functions crucial for effective cell-mediated immune responses

Highlights

Engagement of mature T cell receptor (TCR), a multiprotein complex consisting of an αβ heterodimer associated with invariant CD3 signaling proteins, on CD4+CD8+ double positive (DP) thymocytes by selfpeptide/self-MHC complex on thymic stromal cells results in negative selection of thymocytes expressing strong affinity TCRs and positive selection of thymocytes expressing weak affinity TCRs
Two observations suggest that kinetic signal strength model alone cannot explain the CD4 helper versus CD8 cytotoxic lineage choice; (a) constitutive CD8 or chimeric CD8.4 redirects only a fraction of MHCI-signaled thymocytes into CD4 lineage [14] and (b) positively selected MHCI-restricted thymocytes expressing strong affinity TCR such as OTI- TCR and P14TCR, which transduce stronger signal compared to several MHCII-specific TCRs such as OTII-TCR, fail to develop into the CD4 helper lineage [15]
It is proposed that signal disruption renders MHCI-signaled thymocytes sensitive to cytokine signaling critical for Runx3 activation and the CD8 cytotoxic lineage choice [16,17], while stronger TCR signal induces ThPOK (Zbtb7b, cKrox) in MHCII- signal thymocytes essential for the CD4 helper lineage choice [18]

Summary

Introduction

Engagement of mature T cell receptor (TCR), a multiprotein complex consisting of an αβ heterodimer associated with invariant CD3 signaling proteins, on CD4+CD8+ double positive (DP) thymocytes by selfpeptide/self-MHC complex on thymic stromal cells results in negative selection of thymocytes expressing strong affinity TCRs and positive selection of thymocytes expressing weak affinity TCRs. Two observations suggest that kinetic signal strength model alone cannot explain the CD4 helper versus CD8 cytotoxic lineage choice; (a) constitutive CD8 or chimeric CD8.4 (cytoplasmic domain of CD8 substituted by that of CD4) redirects only a fraction of MHCI-signaled thymocytes into CD4 lineage [14] and (b) positively selected MHCI-restricted thymocytes expressing strong affinity TCR such as OTI- TCR and P14TCR, which transduce stronger signal compared to several MHCII-specific TCRs such as OTII-TCR, fail to develop into the CD4 helper lineage [15].

Results

Conclusion