CD5: A safeguard against autoimmunity and a shield for cancer cells

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The CD5 molecule has been discovered 30 years ago,and although much knowledge has been gained since then about its signalling functions in lymphocytes , 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.

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. 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. All peripheral blood T-cells are CD5hi with CD5 expression at least tenfold that observed on normal CD5+ B-cells. CD5 can thus be used as a marker to monitor the presence of residual T-cells in a negatively-selected B-cell preparation. CD5 is considered as a pan-T-cell marker although as discussed below, its expression may fluctuate. Contrary to mice in which CD5 expression delineates a specific B1a lineage its expression is heterogeneous on human B cells.

CD5 is absent from “conventional” B2 B-cells endowed with a diversified repertoire recognizing T-dependent-TD-antigens, with the exception of transitional immature cells which leave the bone marrow to colonize secondary lymphoid organs. These cells probably represent the first wave of cells that circulate following bone marrow transplantation. In peripheral blood, CD5+CD19+ cells represent 10–15% of B-cells (1% of lymphocytes) in the adult, up to 80% (8–10% of lymphocytes) in the newborn and decrease progressively with age. Most of these CD5+CD19+ cells are naïve and represent either transitional B-cells or B1a-like Bcells able to respond to T-independent-TI-antigens).

However a sizeable fraction, up to 25%, of CD5+ B-cells in the blood co express the memory associated molecule CD27 suggesting that CD5 is an activation marker. These cells are most likely a mixture of TI and TD activated B-cells. CD5 expression can be induced on B-cells in vitro. The optimal activating condition require simultaneous stimulation of both the BCR and the CD40 surface molecules, although IL-6 and the polyclonal activator staphylococcus aureus Cowan strain (SAC) also stimulate CD5 expression on B cells. In summary, CD5 is a marker of some TI/B1-like B cells but can also be induced on B2 B-cells.

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 TCRmediated T-cell proliferation. 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. Of note also is the fact that CD5 is phosphorylated on tyrosine upon TCR-engagement. By establishing CD5 “KO” mice, Tarakhovsky et al., demonstrated that although T-cell development was unaffected, CD5- null T-cells became hyperresponsive to CD3-TCR stimulation. This resulted in increased proliferation and, at the signalling level, these T-cells displayed a strong increase in the tyrosine phosphorylation of both PLCγ-1 and LAT.

Increases of the p23- TCR-zeta chain, and in cytosolic Ca2+ release were also observed. Whether CD5 tyrosine-phosphorylation is necessary to achieve the above functions was not demonstrated in T-cells, contrary to B-cells (see below). After CD3 stimulation, CD5 is also heavily phosphorylated on serine residues, as the CD5 cytoplasmic tail contains at least 5 consensus sites for serine/threonine phosphorylation. It should be mentioned that the specific functions of these domains are at present unclear. In B-cells, the “KO” model established the CD5 as a negative regulator of the BCR; Peritoneal B-1 cells from CD5- null animals indeed respond better to anti-IgM stimulation but not to LPS or CD40 stimulation pointing to the privileged interaction between CD5 and the BCR. Furthermore, CD5 coprecipitates with the BCR complex and it is likely that following interaction with its antigen, the BCR moves to lipid rafts and meets CD5.

This is in agreement with the observation that CD5-cross-linking before BCR-stimulation restores the proliferative activity of B-1 cells, likely through moving away the inhibitory CD5 from the BCR very much like what is seen in T-cells under CD5-cross link followed by TCR stimulation. The molecular events associated to CD5 phosphorylation have been studied in our laboratory. It appears that following BCR engagement a critical tyrosine residue is needed in order to inhibit BCR-mediated early signalling events such as Ca2+ release and MAP kinase activation.

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 . In addition, the specific role of CD5 and IL-10 in the protection from autoimmunity has been demonstrated in vivo. The HEL anti-HEL model: This is a well-established model of B-cell tolerance. In these mice, most B-cells express a transgene encoding a receptor for the T-dependent antigen Hen Egg Lysozyme. Because HEL is artificially expressed in these mice, it is seen as an autoantigen.

Bcells thus meet their cognate antigen during development, yet fail to be deleted and instead become anergic to HEL and express CD5. The role of CD5 in the induction of anergy was demonstrated in an elegant experiment where double (HEL and BCR) transgenic mice were bred into a CD5-null background. By contrast to CD5+ animals, these mice developed haemolytic anemia and responded strongly to HEL. This demonstrate that CD5 is necessary to maintain anergy in B-cells, thereby inducing tolerance to self, but whether CD5-null mice lacked IL-10 was not investigated in this study. However in most models, the protective role of B-cells from autoimmunity has been linked at least in part, to their production of IL-10.The role of regulatory B-cells as inhibitors of autoimmune responses and inflammation but also as potentially harmful cells in cancers has been reviewed recently.Experimental Autoimmune Encephalitis (EAE): In this model which mimics to some extent multiple sclerosis in human, the disease is exacerbated in B-cell-deficient mice pointing to a regulatory function of endogenous B-cells.

Furthermore, the regulatory contribution of B-cells has been linked to their ability to produce IL-10  notably because adoptively transferred B-cells from wild type but not from IL-10-null mice controlled the disease. Inflammatory bowel disease IBD: IL-10 null mice were the first experimental model of spontaneous IBD and since then, other models have been established. Interestingly, IL-10-producing B-cell subsets were identified which regulate inflammation during experimental colitis.

Upregulation of CD5 on T-cells protects from autoimmunity in EAE 1EAE 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). 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 antigen-processing compartment of DC and helped loading MOG peptide onto MHC class-II molecules. These, so called Dalloul “steady state DC”, prevented subsequent EAE development after MOG and adjuvant injection. The cellular mechanism uinderlying this protection involved induction of MOG-specific tolerant CD4+ T-cells.

Furthermore the only surface antigen upregulated on tolerant T-cells in comparison to immune T-cells was CD5. The authors demonstrated that tolerance required CD5 as it was abolished by injection of anti-CD5 MAb, and even more convincingly by breading CD5-null anti-MOG TCR transgenic mice. These mice contrary to CD5+ animals remained responsive to MOG. However, and in contrast to the B-cell HEL/antiHEL model, CD5hi T-cells remained highly responsive to TCR engagement and thus, were not intrinsically anergic.

The role of B-cells and tumour-infiltrating T-lymphocytes

(TIL) in the immune response to tumours  B-cell depletion can enhance immune responses to some tumours. 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 Tcell immunity characterized by the production of IFNgamma. 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. Whether the latter population acts through systemic production of cytokines need to be more substantiated.  Tumour-infiltrating T-cells: TIL have been isolated from lung carcinomas and compared to peripheral blood T-cells through the generation of T-cell clones from these two sources.

Only clones derived from CD8+ TIL, were able to lyse autologous tumour cells in vitro. Whereas lytic and non-lytic clones were comparable for all markers, CD5 was expressed at lower levels on TIL than on PBL T-cells. Although both lytic and non-lytic clones stably adhered to tumour cells, only CD5+ TIL but not CD5hi T-cells elicited a Ca2+ response. This parallels our own experiments in which a Ca2+ response was elicited in anti-IgM-stimulated CD5-negative but not in stimulated CD5+ B-cells. Furthermore, it appears that the anti-tumour efficacy of T-cells is inversely proportional to their expression of CD5.

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. 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 great deal has been learned in the past 10 years, clarifying our understanding of the signalling functions of CD5 [5] and the genes it regulates, much work remains to get the full picture. Yet, beyond a better comprehension of the regulatory mechanisms of immune responses, such advances could find applications in the treatment of autoimmune diseases and cancers.

Author: Ali Dalloul

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