CD44 has been best characterized as an adhesion receptor engaged by migrating T cells. On activated T cells, CD44 can regulate tethering and rolling interactions with vascular endothelial cells that express HA.13
These findings demonstrate that CD44 could provide an alternative to usage of the selectin family of C-type lectins in initiating the multistep adhesion cascade that leads to the extravasation of lymphocytes from the blood via the endothelium into tissues. The CD44-dependent adhesion mechanism is likely to be most important for the mobilization of effector T cells at sites of infection and inflammation because expression of CD44 is upregulated whereas L-selectin (CD62L), the lymphocyte-expressed selectin, is downregulated. In vitro, CD44 associates with the integrin VLA-4 (α4/β1; CD49d/CD29) in the membrane of activated T cells through its cytoplasmic tail, and in vivo this receptor combination can regulate T-cell extravasation into the peritoneum after induced inflammation.14,15
The association between the two surface receptors thereby not only allows for firm adhesion, but also could provide each with access to the other's signaling pathways, which would otherwise be unavailable. Deletion of the cytoplasmic tail of CD44 prevents firm adhesion of cells to the endothelium, highlighting the importance of the molecules' association for T-cell extravasation. The VLA-4-ligand, VCAM-1, is induced on endothelial cells in response to inflammatory cytokines and HA synthesis and expression are also augmented. However, CD44-dependent tethering/rolling could also occur independently of HA via binding to E-selectin, which is expressed on activated endothelium.16
However, we and others have shown that CD44-independent mechanisms can also regulate effector T-cell recruitment to sites of inflammation or tumor implantation because CD44-deficiency does not impair migration.4,17
The major alternative pathway is the binding of P-selectin glycoprotein ligand-1, a selectin-ligand expressed on T cells, to E and/or P selectin, which are induced on inflamed endothelium.18,19
The relative dominance of CD44 or selectins in regulating effector T-cell migration appears to be associated with environmental cues that include the magnitude and duration of inflammation.
In addition to the well-established role of mediating T-cell extravasation, CD44 also has a crucial function in regulating cell motility within the tissue stroma. In tissue-resident T cells, CD44 and other adhesion receptors accumulate at the trailing edge, or uropod, that is the part of the cell body that is in contact with the ECM.20,21
Interactions of ERM (ezrin/radixin/moesin) proteins with the cytoplasmic tail of CD44 can contribute to the stabilization of a polarized cell shape that is necessary for migration. ERM proteins regulate cytoskeletal organization through interactions with actin22
and are involved in the generation of the uropod of a migrating T cell.23
A recent study highlighted the importance of CD44-mediated polarity on interstitial migration in a cancer model, where anti-tumor activity of Cd44-/-
CD8 T cells was compromised as a consequence of defective migration.17
Thus, CD44 expression in T cells in the interstitial space may be essential to maintain cell shape during active migration. As movement takes place, CD44 anchorage of the cell's uropod to the ECM is disengaged by proteolytic activity. Cleavage of the extracellular domain (ECD) of CD44 is mediated by membrane type metalloproteinases (MT1-MMP) on responding T cells.24
In tumor cells, metalloproteinases belonging to the ADAM (a disintegrin and metalloproteinase domain) family play an important role in ECD cleavage.25
Unlike in T cells, CD44 localizes at the leading edge of the cell and is cleaved by ADAM-17, which allows for the redistribution of both molecules and movement of the cell. The resulting extension of the cell was proposed to upregulate Ca++
-induced ADAM-10 activation in the uropod, where cleavage of CD44 and detachment from the ECM subsequently occur.26
It is unknown if ADAM-10 and −17 have similar roles in T cells, especially since CD44 seems to be primarily located in the uropod.20,21
However, through its interaction with CD49d, CD44 may gain access to the leading edge of activated, migrating T cells where it would be able to interact with ADAM-17.14
The release of soluble CD44 ECD could regulate the ability of T cells to interact with the ECM during migration by inhibition of CD44-dependent cell-cell and cell-matrix interactions.27
Cleavage of CD44 ECD initiates the intra-membrane cleavage and release of the intracellular domain (ICD) by presenilin-1/γ secretase.28,29
The resulting cytoplasmic fragment translocates to the nucleus where it may be directly or indirectly involved in gene transcription.30
At least one of the targets of the ICD is the transcriptional co-activator CBP/p300 and activation results in part in the upregulation of Cd44
itself and de novo CD44 production.28
Whether this occurs in T cells is also unknown.
Thus, CD44 can function to mediate entry of T cells to target sites, as well as cell motility within these tissues. The rapid activation and proteolytic degradation of CD44 could allow efficient cell migration and as such is crucial for the potency of T cell effector functions.