Multifaceted regulation of T cells by CD44

Abstract

CD44 is a widely-expressed adhesion receptor that is associated with diverse biological processes involving migrating cells, including inflammation, angiogenesis, bone metabolism, and wound healing. In the immune system, CD44 is upregulated after activation of naive T lymphocytes during their responses against invading microbes. Once an infection is cleared, elevated levels of CD44 remain on the surface of memory T cells that mediate protection against re-infection. While this has led to the use of highly sustained CD44 expression on T cells as an indicator of a previous immune response, the relevance to T-cell responses or homeostasis has been largely unexplored. Our recent studies demonstrate that CD44 selectively regulates the survival of the Th1 subset of CD4 T cells, but not other T-cell subpopulations. These findings, together with studies of CD44 in other cell types, suggest that differences in the engagement of signaling mechanisms are likely to underlie differential regulation of T-cell responses and underscore the importance of this adhesion receptor to immune cell regulation and protection against viruses and intracellular bacteria.

Acknowledgements

Mia Deiro and Dr Roberto Tinoco for critical evaluation of the manuscript. This work was supported by grants from NIH (AI061615 and AI046530) to L.M.B.

Figures and Tables

Figure 1 Potential mechanisms by which CD44 can modulate cell death. (A) CD44 may inhibit apoptosis by sequestering FAS and thereby preventing assembly of death-inducing signaling complex (DISC). Without DISC formation, Fas ligand (FasL) cannot engage FAS, which precludes downstream activation of caspases that would lead to apoptosis. (B) Ligation of CD44 (e.g., through HA) can facilitate aggregation of CD44-integrin-kinase signaling components in lipid rafts. Src family kinases, such as Lck, associate with the cytoplasmic tail of CD44 and activate the PI3K/Akt signaling pathway. Alternatively, binding of either CD44 or VLA-4, which form a heterodimer at the cell surface, could activate PI3K through FAK. Activation of PI3K/Akt is associated with cell survival. Akt can inhibit Fas-mediated CD4 T-cell death by interfering with DISC assembly. In addition, the mTOR pathway may be engaged to support the survival and expansion of T cells.