CD5: A safeguard against autoimmunity and a shield for cancer cells
Introduction
The CD5 molecule has been discovered 30 years ago [1], [2], and although much knowledge has been gained since then about its signalling functions in lymphocytes [3], [4], [5], this molecule remains an important field of investigations. This is notably due to the demonstration that CD5 participates to the immune regulatory network which control autoimmune processes and protects against autoimmunity. Therefore, understanding both how CD5 expression is regulated in lymphocytes and what is the nature of signals, either intracellular or cytokine-mediated, delivered by this molecule in order to hold harmful lymphocytes at bay is worth investigating.
Section snippets
Expression and regulation of CD5 on lymphocytes
CD5 is a pan-T cell marker the expression of which increases in parallel with that of the CD3/TCR complex during T-cell development in the thymus, reviewed in [5]. CD5 can be expressed on all lymphocytes but NK cells, furthermore, although CD5 is expressed on the earliest thymic progenitors, it is lost in NK-committed progenitors whereas it is present on T- and B-cell-committed progenitors [5]. All peripheral blood T-cells are CD5hi with CD5 expression at least tenfold that observed on normal
CD5 as a negative regulator of TCR and BCR signalling
CD5 was initially described as a costimulator of the TCR engagement, inasmuch as CD5 antibodies can boost TCR-mediated T-cell proliferation [21], [22]. The molecular mechanisms underlying T-cell stimulation are still unclear but may involve an indirect interaction of CD5 with ZAP-70 through the binding to TCR-p21 zeta chain in human thymocytes [23]. Of note also is the fact that CD5 is phosphorylated on tyrosine upon TCR-engagement [24].
By establishing CD5 “KO” mice, Tarakhovsky et al.,
CD5-regulated gene expression
In order to better understand the possible role of CD5 in B-cells, we introduced CD5 into Burkitt-derived CD5-negative, Daudi B-cells and selected the transfected clones for high CD5 expression. CD5-transfected cells responded poorly to stimulation with F(ab)'2 anti-IgM in comparison to control—vector only—transfected, cells [8] as expected from previously published data; However when analysing the production of IL-10, a cytokine produced by normal CD5+ B-cells, we observed that CD5-transfected
Both enhanced expression of CD5 on B-cells, and B-cell produced IL-10 protect from autoimmune diseases
The role of CD5-expressing B-1a cells in autoimmunity has been described in detail [31] especially their propensity to produce high levels of IL-10. This property together with their production of natural IgM endowed with low affinity and polyreactivity for autoantigens, suggest that B-1a cells protect from autoimmunity likely by removing autoantigens and apoptotic cells [32]. In addition, the specific role of CD5 and IL-10 in the protection from autoimmunity has been demonstrated in vivo.
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The
Upregulation of CD5 on T-cells protects fromautoimmunity in EAE
1) EAE is a good model of human multiple sclerosis; this disease can be induced in mice upon injection of myelin oligodendrocyte glycoprotein (MOG) and Freund's complete adjuvant. In an elegant study, Nussenzweig's group prevented the disease by injecting mice with tolerogenic dendritic cells, (DC) [36]. To achieve this, the authors used a hybrid Ab capable to target simultaneously MOG and DEC-205, an endocytic receptor highly expressed by DC. This receptor carried MOG into the
The role of B-cells and tumour-infiltrating T-lymphocytes (TIL) in the immune response to tumours
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B-cell depletion can enhance immune responses to some tumours [34]. This was demonstrated by injection of wild type or B-cell-deficient mice with various tumours. Whereas wild type mice are unable to control tumour growth, B-cell-deficient animals elicit tumour-specific T-cell immunity characterized by the production of IFN-gamma. This production is inhibited by B-cells or by rIL-10. Thus B lymphocytes are detrimental to anti-tumour immunity, however B-cells seldom infiltrate solid tumours.
Conclusions and perspectives
A number of human and animal studies indicate that in certain conditions, autoantigens, antigen-presenting cells APC, cytokines or stromal cells from tumours regulate the expression of CD5 on T- and B-cells. CD5 is upregulated on “tolerogenic” lymphocytes from either the T or the B-lineage the latter being regulatory B-cells [34]. This avoids uncontrolled over reactivity to self antigens but may be harmful in cancers as it inhibits the killing of malignant cells by the immune system. Although a
Take-home messages
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CD5 prevents T- and B-lymphocytes from uncontrolled self reactivity.
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CD5 inhibits TCR and BCR early signalling events; CD5-positive B-cells, protect from autoimmunity by production of cytokines such as IL-10.
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The “tolerogenic” effect of CD5 prevents tumour-infiltrating lymphocytes from lysing malignant cells.
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Inducing CD5 expression on lymphocytes may be protective in autoimmune diseases, conversely, inhibiting CD5 expression on tumour-infiltrating-lymphocytes may help CD8+ T-cells to kill
Acknowledgements
Fathia Mami-Chouaib and Marie-Christine Béné are acknowledged for helpful comments.
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