T-cell homing specificity and plasticity: new concepts and future challenges

doi:10.1016/j.it.2006.03.007

Trends in Immunology

Volume 27, Issue 5, May 2006, Pages 235-243

https://doi.org/10.1016/j.it.2006.03.007 Get rights and content

Naive and effector/memory T cells have distinct repertoires of trafficking ligands and receptors that restrict their ability to interact with specialized microvessels in different anatomical compartments and, consequently, have distinct patterns of migration. Antigen-experienced lymphocytes can be further subdivided into different subsets based on their expression of characteristic sets of trafficking receptors that favor their accumulation in certain target organs, including the skin and gut. Here, we summarize recent advances that have broadened our understanding of the cellular and molecular events that induce the generation of tissue-specific effector/memory T cells and discuss how these mechanisms could be harnessed for the therapeutic manipulation of T-cell-dependent pathologies.

Introduction

To perform their immunological functions, T cells must exit the blood and enter into different tissues in the body. An essential step in this process is their adhesion to the endothelium of postcapillary venules, a complex, multi-step cascade of events mediated by various adhesion receptors [1]. Although the multi-step paradigm applies to all leukocytes, the molecules involved in the different steps vary depending on the leukocyte population, the target tissue and the inflammatory context [1] (Table S1 in the online supplementary material). Recent advances in the field have unveiled several examples of this exquisite degree of specialization, in particular, for T-cell migration. Indeed, many T-cell subsets express unique patterns of homing molecules to interact with organ-specific microvascular endothelial cells for preferential recruitment to distinct target tissues. Recent observations highlight a previously unexpected degree of dynamic plasticity in the trafficking behavior of effector/memory T cells. These findings open the possibility that the expression of tissue-specific molecules on lymphocytes could be reprogrammed and custom-modified to tailor cellular immune responses for therapeutic purposes.

Section snippets

Migration of effector/memory T cells: what can T cells remember from their past experiences?

Naive T cells preferentially migrate to secondary lymphoid organs (SLO), including peripheral or mesenteric lymph nodes (PLN or MLN), Peyer's patches (PP) and the spleen, which are the sites where T cells first meet their cognate antigen and become activated if they encounter appropriate co-stimulatory signals. Antigen-experienced T cells are more diverse than naive T cells with respect to their migratory properties. In particular, effector/memory cells migrate to a greater extent to

Tissue-specific homing receptors: distinct ‘zip codes’ to shape immune responses

T_EFF and T_EM share, by definition, the inability to migrate to sites that require CCR7 and L-selectin expression (i.e. SLO other than the spleen), but they are by no means homogeneous with respect to their preferred tissue targets. Major T_EFF and T_EM subsets have been identified that show remarkable migratory selectivity for certain organs, including the gut and skin (Figure 2a; Table S1 in the online supplementary material). Murine cutaneous T_EFF and T_EM express E- and P-selectin ligands [13]

How effector/memory T cells learn where to go – the instructive role of dendritic cells

In humans, the site of antigen entry strongly influences the traffic pattern of T_EFF. Pathogens entering through the skin, for example, herpes simplex virus, preferentially prime lymphocytes with skin homing receptors 42, 43, 44; by contrast, oral vaccination induces higher levels of α4β7 on effector/memory T cells (suggesting homing to the gut) than intramuscular or subcutaneous administration of the same antigen 45, 46, 47. Importantly, among memory CD8⁺ T cells, only α4β7⁺ (but not α4β7⁻)

Imprinting mechanisms for gut-homing T cells

The imprinting mechanism for gut-homing T cells was uncovered by Iwata et al. [67], who analyzed vitamin A-deficient mice. These animals had dramatically reduced numbers of effector/memory T cells in the gut mucosa, but the T-cell compartment remained unaffected elsewhere [67]. Experiments in vitro showed that the presence of the vitamin A metabolite retinoic acid (RA) during T-cell activation induces α4β7 and CCR9 and reduces the upregulation of CCR4 mRNA, even in the absence of DCs. RA also

Plasticity in T-cell homing: reprogramming T cells to reach new horizons

There is mounting evidence that the tissue commitment of effector/memory lymphocytes is often reversible. For example, human CD4⁺ T cells can sequentially up- or downregulate the skin homing receptor CLA (an E-selectin ligand) when they are reactivated under Th1 or Th2 conditions, respectively [63]. In addition, effector/memory CD8⁺ T cells isolated from intestinal mucosa were inefficient at homing back to the gut [74]. Indeed, although α4β7 is needed for efficient T-cell homing to the

Future directions

A growing body of evidence indicates that the division between T_CM and T_EFF/T_EM can be complex and fluid, at least with respect to immunological function. Aside from the presence or absence of CCR7 and L-selectin, respectively, additional universally accepted criteria for unambiguous distinction between these T cell subsets remain lacking. In vitro, T_CM-like cells can be produced from antigen-primed naive CD4⁺ precursors by exposing them to a short, non-polarizing antigenic stimulus [36], or

Acknowledgements

Supported by NIH grants HL62524, HL54936, HL56949, AI-061663 and a Career Development Award from the Crohn's and Colitis Foundation of America.

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Trends in Immunology

T-cell homing specificity and plasticity: new concepts and future challenges

Introduction

Section snippets

Migration of effector/memory T cells: what can T cells remember from their past experiences?

Tissue-specific homing receptors: distinct ‘zip codes’ to shape immune responses

How effector/memory T cells learn where to go – the instructive role of dendritic cells

Imprinting mechanisms for gut-homing T cells

Plasticity in T-cell homing: reprogramming T cells to reach new horizons

Future directions

Acknowledgements

Immunity

Immunity

Cell

Blood

Immunity

Gastroenterology

Lab. Invest.

Blood

Virology

Immunity

Cell

Blood

Blood

Immunity

Immunol. Today

Immunol. Today

Immunity

Blood

T-cell function and migration. Two sides of the same coin

New Engl. J. Med.

Preferential localization of effector memory cells in nonlymphoid tissue

Science

Migratory properties of naive, effector, and memory CD8+ T cells

J. Exp. Med.

Two subsets of memory T lymphocytes with distinct homing potentials and effector functions

Nature

CXCL12 mediates CCR7-independent homing of central memory cells, but not naive T cells, in peripheral lymph nodes

J. Exp. Med.

Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells

Nat. Immunol.

Effector differentiation is not prerequisite for generation of memory cytotoxic T lymphocytes

J. Clin. Invest.

Lineage relationship and protective immunity of memory CD8 T cell subsets

Nat. Immunol.

Cutting edge: CCR7+ and CCR7− memory T cells do not differ in immediate effector cell function

J. Immunol.

In vivo differentiated cytokine-producing CD4+ T cells express functional CCR7

J. Immunol.

Initial T cell frequency dictates memory CD8+ T cell lineage commitment

Nat. Immunol.

ELAM-1 is an adhesion molecule for skin-homing T cells

Nature

The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells

Nature

CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells

Proc. Natl. Acad. Sci. U. S. A.

CD4+ T cells migrate into inflamed skin only if they express ligands for E- and P-selectin

J. Immunol.

CC chemokine receptor (CCR)4 and the CCR10 ligand cutaneous T cell-attracting chemokine (CTACK) in lymphocyte trafficking to inflamed skin

J. Exp. Med.

CCL27-CCR10 interactions regulate T cell-mediated skin inflammation

Nat. Med.

Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation

J. Pathol.

A skin-selective homing mechanism for human immune surveillance T cells

J. Exp. Med.

Critical role for β7 integrins in formation of the gut-associated lymphoid tissue

Nature

Migratory properties of naive, effector, and memory CD8⁺ T cells

Cutting edge: CCR7⁺ and CCR7⁻ memory T cells do not differ in immediate effector cell function

In vivo differentiated cytokine-producing CD4⁺ T cells express functional CCR7

Initial T cell frequency dictates memory CD8⁺ T cell lineage commitment

CD4⁺ T cells migrate into inflamed skin only if they express ligands for E- and P-selectin