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Akin to CD69 regulated surface expression of S1P1 on recently activated T cells, T cell receptor signaling the first signal of T cell activation has been reported to induce transcriptional downregulation of S1P1 8. Transcriptional restoration of S1P1 is also likely to regulate T cell egress during an immune response.
Upon antigen recognition, activated T cells downregulate CCR7 Fibroblastic reticular cells within the LN produce CCL21 and help generate a gradient where CCL21 levels are highest toward the LN center and decrease toward the peripheral medullary areas 25 , In addition to mediating intranodal positioning, migration, and motility 75 , CCR7 also confers T cell retention within LNs Adhesion Molecules Involved in Egress across Sinuses While it is well established that adhesion molecules and their integrin ligands play an important role in T cell entry into LNs through HEVs , not much is known about their role in T cell egress across lymphatic sinuses.
A role for leukocyte function-associated antigen 1 LFA-1 in delaying egress of T cells across lymphatic sinuses has recently been suggested. However, the in vivo involvement of these receptors in LN egress has not been demonstrated thus far. Such studies have confirmed previous histology-based studies showing that T cell migration and egress occurs both at the level of the cortical and medullary sinuses 23 , In cortical sinuses without flow, T cells migrated at the same speed as those in the parenchyma and occasionally exited sinuses back into the LN parenchyma 23 , In larger cortical sinuses with flow, T cells were more rounded, shared fairly uniform velocities, and had a lower frequency of exit back into the parenchyma 23 , T cells in the macrophage-rich medullary sinuses appeared to become poorly mobile and occasionally exited the sinuses and returned to the T cell zone Following migration of T cells through cortical and medullary sinuses, T cells were released into the subcapsular region near the efferent vessel and moved off rapidly with lymph flow Overall, T cell transit time through the LN appears to be determined by random walk encounters with lymphatic sinuses Only at the level of the sinus do S1P1-expressing T cells start to sense S1P in lymph, which triggers their exit into the lymphatic compartment 22 — Although several molecules involved in T cell egress through afferent LVs have recently been identified, we still know fairly little about this process, particularly at the single-cell level.
Interestingly, these findings have revealed that migration into and within afferent LVs occurs in a stepwise fashion: DCs enter LVs at the level of lymphatic capillaries and then crawl in a semi-directed manner within lymphatic capillaries — Only once they have reached contracting lymphatic collectors do cells switch from an active to passive mode of movement, i. Similarly, neutrophils were recently found to actively crawl within dermal lymphatic capillaries Although not demonstrated so far, it is therefore likely that T cell migration through lymphatic capillaries also involves an active, intraluminal crawling step Figure 1 A.
In the following section, important molecules involved in T cell migration from the skin to the dLN will be discussed in greater detail see also Table 2. However, in humans, CCR7 is expressed on the majority of T cells in blood, including those that express adhesion molecules required for homing to non-lymphoid tissue Although CCR7 appears to be crucial for T cell exit from homeostatic and acutely inflamed skin, its contribution to T cell exit from chronically inflamed skin appears to be more limited 11 , By contrast, the exact contribution of CCR7 to T cell migration through afferent lymphatics has not been addressed so far.
This suggests that acute inflammation might induce T cell retention in the tissue. This upregulation occurs in a stimulus-specific manner and may serve to fine-tune leukocyte recruitment into LVs. Although not specifically studied so far, changes in the chemokine expression profile of LECs might also explain the reduced CCR7 and S1P dependence of T cell tissue exit observed from chronically but not from acutely inflamed skin On the other hand, it has to be considered that most studies investigating T cell tissue exit have been performed using adoptively transferred T cells, which might not completely reflect the chemokine or adhesion molecule requirements of endogenous T cells.
The MR 82 , which has been shown to mediate T cell binding to lymphatic sinuses in LNs 82 , is also expressed on efferent and afferent LVs , Whether VCAM-1 might more broadly support T cell migration through afferent LVs in the context of tissue inflammation remains to be determined.
However, it is noteworthy that P-selectin is also upregulated on afferent LVs during contact hypersensitivity-induced inflammation This raises the question whether inflammation-induced selectins and their ligands might play a role in T cell exit under inflammatory conditions. Braun and colleagues investigated this entry pathway by performing time-lapse imaging in the popliteal LN following microinjection of T cells directly into the cannulated afferent LV On the other hand, T cells injected after pre-injection of DCs now transmigrated the SCS floor on the afferent side of the LN and avidly migrated inward at sites of DC transmigration These findings suggested that DCs induced local changes in the SCS floor during transmigration that facilitated direct entry of T cells into the LN parenchyma.
Considering that afferent lymph typically contains both T cells and DCs that arrive simultaneously in the subcapsular space, it will be interesting to further explore LN entry from afferent LVs in an endogenous setup. Other studies have suggested that T cells might enter the LN parenchyma directly through the SCS: as early as 4 h after adoptive transfer into the footpad of mice, T cells could be detected within the LN parenchyma in close proximity to the SCS 13 , Moreover, macrophage scavenger receptor 1, a molecule expressed on LECs of the SCS, but not on the medullary or cortical sinuses, was recently found to regulate lymphocyte entry into the LN parenchyma This generates a sort of molecular sieve that restricts the access of soluble antigen into the conduit system and hence into the LN parenchyma.
Purpose of T Cell Migration through Afferent LVs As we gain more insight into T cell trafficking through LVs, our knowledge regarding the biological significance of this migratory process continues to grow. Blocking this important migratory step, e. On the other hand, recent data indicate that T cell trafficking through afferent LVs may not only occur to promote immune surveillance but may additionally have immune-dampening effects and serve to avoid overshooting T cell-mediated inflammatory responses.
In the following section, these hypotheses shall be discussed in greater detail. Role of T Cell Circulation through Afferent LVs in Immune Surveillance T cell recirculation through afferent LVs is thought to contribute to immune surveillance by constantly replenishing the T cell pool in peripheral tissues with new antigenic specificities. However, increasing evidence suggests that recirculating T cells do not provide complete protection of peripheral tissues, and that TRM play a more important role in this process , Although there is some evidence that TRM proliferate locally, it is unknown whether TRM are ever replaced by circulating T cells , , The relative contribution of resident and circulating T cells in pathogen clearance remains unknown and might be highly context dependent, e.
Role of Treg Tissue Exit in Controlling Immune Responses in dLNs Previous studies have shown that the local ratio of Tregs to Teff at inflamed sites is a critical determinant for the outcome of inflammation — While these findings suggest that retention of Tregs within peripheral tissue promotes resolution of inflammation, large numbers of Tregs reportedly exit the skin during a cutaneous immune response in mice Several islet allograft survival studies highlight Treg migration to dLNs as a prerequisite for efficient downregulation of the ongoing allograft response 66 — 68 , Only Tregs within the skin, or having previously exited the skin via afferent LVs, reportedly displayed an activated phenotype Upon adoptive transfer of egress-incompetent Treg into the graft, graft survival was shorter than that for WT Tregs 66 — Similarly, in a study using Kaede mice, Tregs that migrated from inflamed skin had an activated phenotype, inhibited immune responses more robustly than LN-resident Tregs, and were able to recirculate back to the skin These findings suggest that Tregs that have exited the skin via afferent LVs restrict LN immune responses and consequently tissue inflammation and recirculate back to inflamed tissue to help further control local immune responses.
Role of Tissue Exit of Bystander T Cells in Resolving Local Inflammation The extent of tissue inflammation often correlates with the number and composition of infiltrating T cells, which itself is dependent on T cell recruitment from blood, survival in the tissue, and, last but not least, on T cell exit through afferent LVs.
Interestingly, two recent studies have shown that the ability of T cells to exit inflamed tissues has an impact on the degree of tissue inflammation. Similarly, T cells overexpressing CCR7 had an enhanced capacity to exit from inflamed skin and accelerated resolution of inflammation While recruitment into tissue is independent of the antigen specificity of T cells , , exit of T cells from inflamed tissues appears to be at least in part antigen dependent , This mechanism is likely in place to reduce unnecessary tissue damage through bystander T cells.
Conclusion and Outlook In addition to cannulation studies, which have for more than six decades provided insights into the cellular composition of lymph, newer techniques such as adoptive transfer studies, LN egress studies or experiments performed in Kaede mice have considerably accelerated our recent gain of knowledge regarding the molecular mechanism of T cell trafficking through LVs.
At the same time, IVM studies have provided further insight into the dynamics of these processes, by visualizing the single-cell behavior and anatomic location of T cell migration toward, across, and within LVs.
While T cell egress from LNs into efferent LVs has been quite intensively studied, we still know comparably little about T cell migration into and within afferent LVs, or about the subsequent T cell entry step into the parenchyma of a dLN. In the future, it will be important to better characterize the distinct T cell subsets migrating through afferent LVs and the molecules involved in their trafficking.
Moreover, the importance of tissue-resident vs. At the same time, it will also be important to carefully chose the right animal models when studying these processes: the fact that only few memory T cells are present in peripheral tissues of laboratory mice held under optimized hygienic conditions, and that these mice respond differently to immunologic challenges in comparison to mice housed under less hygienic environments 74 , indicate that our preferred experimental setups might not represent a faithful model for studying the importance of recirculating vs.
On the other hand, we also still know very little about the potential function of recirculating T cells in dampening acute immune responses, possibly via tissue exit of Tregs or of T cells with irrelevant antigenic specificities. Recent observations that migration of DCs and neutrophils through afferent LVs involves active semi-directed migration within lymphatic capillaries suggest that the migratory process itself is more complex and might serve other purposes than the mere transport of cells to the dLN.
Thus, in spite of recent advances regarding the molecular control of T cell traffic through LVs, we still know little about the biological relevance of these processes, particularly with regard to migration through afferent LVs. Ultimately, more insight into both the molecular mechanisms and the relevance are expected to contribute to identifying new targets for immunomodulatory therapies.
Author Contributions All the authors jointly wrote the manuscript and prepared the figures. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. K and E. Exhausted T cells lose robust effector functions, express multiple inhibitory receptors and are defined by an altered transcriptional programme.
T cell exhaustion is often associated with inefficient control of persisting infections and tumours, but revitalization of exhausted T cells can reinvigorate immunity. Here, we review recent advances that provide a clearer molecular understanding of T cell exhaustion and reveal new therapeutic targets for persisting infections and cancer.
During acute infections or vaccinations, naive T cells are activated and differentiate into effector T cells over the course of 1—2 weeks 1 , 2. This differentiation is accompanied by robust proliferation, transcriptional, epigenetic and metabolic reprogramming, and the acquisition of cardinal features of effector T cells such as effector function, altered tissue homing and dramatic numerical expansion 1 , 2.
Following the peak of effector expansion, the resolution of inflammation and the clearance of antigen, most activated T cells die, but a subset persists and transitions into the memory T cell pool.
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