Trends in Immunology
T-cell homing specificity and plasticity: new concepts and future challenges
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
TEFF and TEM 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 TEFF and TEM 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 TEFF and TEM 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 TEFF. 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 TCM and TEFF/TEM 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, TCM-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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