Endothelial-binding, proinflammatory T cells identified by MCAM (CD146) expression: Characterization and role in human autoimmune diseases

Abstract

A subset of T cells defined by the cell surface expression of MCAM (CD146) has been identified in the peripheral circulation of healthy individuals. These cells comprise approximately 3% of the pool of circulating T cells, have an effector memory phenotype, and are capable of producing several cytokines. Notably, the MCAM positive cells are enhanced for IL-17 production compared to MCAM negative effector memory T cells. These call are committed for IL-17 production and do not require in vitro polarization with exogenous cytokines. MCAM positive T cells also demonstrate an increased ability to bind to endothelial monolayers. In numerous autoimmune diseases these cells are found at increased proportions in the peripheral circulation, and at the sites of active inflammation in patients with autoimmune disease, these cells appear in large numbers are major contributors to IL-17 production. Studies to date have been performed with human subjects and it is uncertain if appropriate mouse models exist for this cells type. These cells could represent early components of the adaptive immune response and serve as targets of therapy in these diseases, although much work remains to be performed in order to discern the exact nature and function of these cells.

An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition

“…CD146 (also called melanoma cell adhesion molecule [MCAM]) is a cell adhesion glycoprotein expressed on lymphoid cells, endothelial cells, smooth muscle cells, and tumor cells, and displays homophilic or heterophilic interaction (50). It has been shown to play a major role in T cell migration through interaction with endothelial cells (33,43).…”

Blockade of MCAM/CD146 impedes CNS infiltration of T cells over the choroid plexus

“…Apart from LFA-1–ICAM-1-dependent penetration of the CP by T H 17 cells, we have recently shown that adhesion of T H 17 cells to an in vitro model of the BBB in the absence of VLA-4 involves melanoma cell adhesion molecule (MCAM; CD146) [ 17 ]. MCAM is an extracellular adhesion molecule broadly expressed on mesenchymally derived tissues [ 18 ]; in humans it has also been reported to be expressed on a subpopulation of IL-17-secreting CD4 + and CD8 + T cells (T H 17 and Tc17 cells, respectively) [ 18 – 25 ]. EAE experiments performed in endothelial MCAM knockout mice have shown reduced disease severity and reduced T H 17 infiltration into the CNS, supporting a role for this molecule in the entry of encephalitogenic T cells into the brain [ 26 ].…”

CCR6⁺ MCAM⁺ Th17 Cell Numbers Increase in Patients with Psoriasis and Correlate with Disease Severity

“…Moreover, anti-MCAM antibody therapy seemed to be potentially effective for the treatment of various Th17-mediated diseases 22 , suggesting that MCAM could play pathogenic roles in disease. Indeed, the MCAM level in endothelial cells is increased by TNF, and it acts to enhance both angiogenesis and migration of activated monocytes into in amed tissues, suggesting that MCAM may augment the pathogenesis of psoriasis 18 . As shown in Table 1 and Fig.…”