TCRDependent TCell Trafficking

The possibility that Ag location might in some way mediate specific T-cell localization and tissue retention has been suggested by some studies looking at the migration of autoantigen-specific T cells in experimental models of inflammation. The participation of TCR-derived signals in the regulation of T-cell migration was suggested long ago by the observation that TCR triggering can induce integrin activation and immobilize migrating T cells. A role for TCR-triggering by the endothelium (during extravasation) in the regulation of T cell trafficking has also emerged from in vitro studies showing that antigen display by the endothe-lium leads to the recruitment of specific human and murine CD4+ and CD8+ T cells into the tissue. A recent study has provided the first in vivo evidence that insulin-specific CD8+ T cells require antigen presentation by pancreatic microvascular endothelium to gain access to pancreatic islets [1]. These data have been confirmed by our observation that TCR-triggering by the endothelium induces T cell diapedesis without affecting adhesion [2]. The mechanism whereby cognate recognition promotes transmigration has yet to be fully defined, and it is likely to involve TCR-mediated activation of signaling pathways that control adhesion molecule activation and cytoskeletal rearrangements. In this context, recent studies have established a role for adapter proteins such as Vav, ADAP (FYB), and SKAP-

55 in the activation of integrins following TCR triggering. Downstream events in these pathways are likely to involve Ras/Rho family GTPases, including Ras, Rho, Rac, and Cdc42.

Although it is clear that the majority of T-cell recruitment into tissues is regulated by noncognate mechanisms, antigen display by the endothelium can enhance the specificity and efficiency of lymphocyte recruitment into and retention at antigenic sites of inflammation, thus minimizing collateral

No ANTIGEN

(Ol

Transcriptional events: induction

Vorco,"mu''o^andadh'"onmo"cu"s

Tissue invasion by T cells

1

\ + ANTIGEN

A A

Activation?

Oil

Ignorance?

Recruitment of antigen-specific T cells

Figure 2 Functional consequences of T cell-endothelial cell interactions. Sustained interactions with the endothelium during extravasation induce a genetic reprogramming in T lymphocytes leading to upregulation of adhesion and costimulatory molecules. As a consequence, T cells become more tissue-invasive and hyperreactive to antigenic stimuli. The effects of antigen presentation by the endothelium to transiting T cells during extravasation are less clear; however, this event appears to favor the extravasation of antigen-specific T lymphocytes. (see color insert)

Figure 2 Functional consequences of T cell-endothelial cell interactions. Sustained interactions with the endothelium during extravasation induce a genetic reprogramming in T lymphocytes leading to upregulation of adhesion and costimulatory molecules. As a consequence, T cells become more tissue-invasive and hyperreactive to antigenic stimuli. The effects of antigen presentation by the endothelium to transiting T cells during extravasation are less clear; however, this event appears to favor the extravasation of antigen-specific T lymphocytes. (see color insert)

damage caused by excessive antigen-nonspecific inflammatory cells. A summary of the functional effect of T cell-EC interactions discussed here is provided in Figure 2.

References

Bibliography (Further Reading)

Fabbri, M., Bianchi, E., Fumagalli, L., and Pardi, R. (1999). Regulation of lymphocyte traffic by adhesion molecules. Inflamm. Res. 48, 239-246. Kunkel, E. J., and Butcher, E. C. (2002). Chemokines and the tissue-specific migration of lymphocytes. Immunity 16, 1-4. This review clearly highlights the role of chemokines/adhesion molecules in controlling homeostatic lymphocyte trafficking, including the localization of cutaneous and intestinal memory T cells. Luscinskas, F. W., Ma, S., Nusrat, A., Parkos, C. A., and Shaw, S. K. (2002). The role of endothelial cell lateral junctions during leukocyte trafficking. Immunol. Rev. 186, 57-67. This article analyzes the endothelial-dependent mechanisms that coordinate transendothelial migration in and highlights the role of certain lateral junctional proteins and protein complexes. Marelli-Berg, F. M., and Jarmin, S. J. (2004). Antigen presentation by the endothelium: A green light for antigen-specific T cell trafficking? Immunol. Lett. 93, 109-113. This is a critical overview of the often conflicting reports on the functional effects of antigen presentation by endothelial cells to T lymphocytes.

Capsule Biography

Federica Marelli-Berg is a PI in the T Cell Motility Laboratory, Department of Immunology, Imperial College London. The focus of her research revolves on the regulation of T lymphocyte motility, particularly by the interactions with the endothelium.

Was this article helpful?

0 0
Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

Get My Free Ebook


Post a comment