Review
Chemokines and chemokine receptors in T-cell priming and Th1/Th2-mediated responses

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Abstract

T-cell priming occurs in the lymphoid tissue via T cell–dendritic cell interaction. Conversely, delayed-type hypersensitivity or allergic reactions can occur in any tissue, following interaction of T helper 1 (Th1) or Th2 cells with effector leukocytes. Here, Federica Sallusto and colleagues review the role played by chemokines and chemokine receptors in positioning T cells for the immune response.

Section snippets

Chemokines and receptors as critical elements for controlling leukocyte localization

Leukocyte migration is controlled at two critical junctures: first, the arrest and firm adhesion of blood-borne cells on endothelial surfaces and, second, the migration through the endothelium into the interstitium and from there to particular microenvironments. It is clear that chemokines are of fundamental importance for both of these steps. Leukocyte binding to endothelium involves a selectin-mediated rolling followed by an integrin-mediated firm adhesion. It is the chemokines, displayed on

Differential chemokine receptor expression on naive and memory T cells

In early studies on T-cell chemotaxis, a surprising finding was that only memory/activated T cells appeared to respond to the known chemokines, whereas naive T cells did not. This was surprising in view of the fact that lymphocyte migration through lymphoid tissue was known to be blocked by pertussis toxin, which inhibits chemokine receptor signalling7, 8. Thus, the responsiveness to RANTES (Ref. [9]), monocyte chemoattractant protein 1 (MCP-1), MCP-2 and -3 (Refs 10, 11, 12), as well as the

Chemokine receptor expression on Th1 and Th2 cells

In contrast to naive T cells, antigen-experienced T cells are heterogeneous, reflecting their activation state and polarization. The polarization of T cells into type 1 or type 2 represents a central paradigm of T-cell responses21, 22, 23. The combination of cytokines present during priming determines the pattern of cytokines produced by the effector T cells (Fig. 2). CD4+ Th1 cells produce interferon γ (IFN-γ) and activate mononuclear phagocytes, thus protecting against intracellular microbes.

Flexibility in chemokine receptor expression provided by IFN-α or TGF-β

Polarization of T cells is regulated by the strength of antigenic stimulation[39], as well as by the cytokines present during priming. These polarizing cytokines are derived from the APCs themselves, the responding T cells or bystander cells40, 41, 42, 43(Fig. 2). Although IL-12 (Ref. [44]) and IL-4 (Ref. [45]) play a major role in Th1- and Th2-cell differentiation, it is clear that the final outcome of T-cell polarization can also be influenced by other cytokines. In humans, IFN-α induces Th1

Chemokines orchestrate T-, B- and dendritic cell encounters in secondary lymphoid organs

The observations reviewed above suggest that chemokines and their receptors play a major role in directing the right cells to the right place. This is well illustrated by the cellular interactions that control the generation of a primary immune response (Fig. 3).

Lymph nodes are specialized sites for T-cell priming because they optimize the interaction between dendritic cells (DCs) and naive T cells[48]. Immature DCs, as well as monocytes, which represent their immediate precursors, express

Regulation of leukocyte migration at sites of delayed-type hypersensitivity (DTH) and allergic reactions

Local inflammation increases leukocyte adhesion to endothelium and transmigration. The basis of this phenomenon is the upregulation of adhesion molecules on endothelial cells and the production of a variety of inflammatory chemokines by endothelial and tissue cells. It is likely that the differential distribution of these molecules will determine which effector cells will be preferentially recruited to particular sites of inflammation[64](Fig. 3).

At sites of DTH reactions, inflammatory

Chemokine receptors for leukocyte co-localization

One can judge a T cell by the company it keeps: Th2 cells co-localize with eosinophils and basophils, whereas Th1 cells are more often associated with macrophages and neutrophils. An emerging principle is that the sharing of chemokine receptors promotes the encounter of antigen-specific T cells with the different classes of effector cells. There are two striking examples: first, the common expression of CCR3 by Th2 cells26, 30, eosinophils[76]and basophils[28]. These three cell types cooperate

Future perspectives

The discovery of numerous chemokines and their receptors has added greatly to our understanding of how lymphocytes traffic selectively through tissues. The obvious task at hand is to define the function and expression pattern of all chemokine receptors to paint a complete picture. The signalling capacity of the various receptors in different cell types is also an important but poorly understood topic. Some receptors can be differentially coupled to downstream signalling pathways and may thus

Acknowledgements

We thank M. Baggiolini, C.J. Gutierrez-Ramos, M. Colonna and K. Karjalainen for critical reading and comments. The Basel Institute for Immunology was founded and is supported by F. Hoffmann-La Roche Ltd.

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