In Vivo Expression Pattern of MICA and MICB and Its Relevance to Auto-Immunity and Cancer

Stéphanie Schrambach,Seiamak Bahram,Jean Sibilia,Vincent Leymarie,Marc Ardizzone,Jacques Zimmer

doi:10.1371/journal.pone.0000518

Stéphanie Schrambach, Seiamak Bahram + Show 4 more

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https://doi.org/10.1371/journal.pone.0000518

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Abstract

Non-conventional MHC class I MIC molecules interact not with the TCR, but with NKG2D, a C-type lectin activatory receptor present on most NK, γδ and CD8+ αβ T cells. While this interaction is critical in triggering/calibrating the cytotoxic activity of these cells, the actual extent of its in vivo involvement, in man, in infection, cancer or autoimmunity, needs further assessment. The latter has gained momentum along with the reported expansion of peripheral CD4+CD28−NKG2D+ T cells in rheumatoid arthritis (RA). We first initiated to extend this report to a larger cohort of not only RA patients, but also those affected by systemic lupus erythematosus (SLE) and Sjögren's syndrome (SS). In RA and SS, this initial observation was further tested in target tissues: the joint and the salivary glands, respectively. In conclusion and despite occasional and indiscriminate expansion of the previously incriminated T cell subpopulation, no correlation could be observed between the CD4+CD28−NKG2D+ and auto-immunity. Moreover, in situ, the presence of NKG2D matched that of CD8+, but not that of CD4+ T cells. In parallel, a total body tissue scan of both MICA and MICB transcription clearly shows that despite original presumptions, and with the exception of the central nervous system, both genes are widely transcribed and therefore possibly translated and membrane-bound. Extending this analysis to a number of human tumors did not reveal a coherent pattern of expression vs. normal tissues. Collectively these data question previous assumptions, correlating a tissue-specific expression/induction of MIC in relevance to auto-immune or tumor processes.

Highlights

Cytotoxic CD8+ and helper CD4+ ab T cells recognize conventional peptide-loaded Major Histocompatibility Complex (MHC) class I and II molecules respectively [1]
Unlike the above mentioned conventional MHC-I molecules, MIC molecules [7,8] do not interact with the TCR per se but do so with NKG2D, a C-type lectin activatory receptor expressed on NK, cd and CD8+ ab T cells [9,10]
This interaction has been shown to over-ride the inhibitory signal provided by Killer Inhibitory Receptors (KIR) and/or CD94/NKG2A/B molecules which sense the presence of respectively HLA-ABC and -E on target cells

Summary

Introduction

Cytotoxic CD8+ and helper CD4+ ab T cells recognize conventional peptide-loaded Major Histocompatibility Complex (MHC) class I and II molecules respectively [1] Whilst the former interaction leads to the elimination of the virally infected or the tumorized target cells, the latter, helps amplify/regulate primarily the humoral immune response against exo or auto-antigens [2,3]. This textbook definition of the adaptive immune response is clear, real life functional/dysfunctional implications of these interactions, in conjunction with the second, innate, actors of the immunity, is far from being simple. Whether this interaction is relevant in autoimmunity is a matter of more recent emphasis [15]

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