Location, location, location: the impact of migratory heterogeneity on T cell function

Abstract

T cell migration is crucial for an effective adaptive immune response to invading pathogens. Naive and memory T cells encounter pathogen antigens, become activated, and differentiate into effector cells in secondary lymphoid tissues, and then migrate to the site(s) of infection where they exert effector activities that control and eliminate pathogens. To achieve activation, efficient effector function, and good memory formation, T cells must traffic between lymphoid and non-lymphoid tissues within the body. This complex process is facilitated by chemokine receptors, selectins, CD44, and integrins that mediate the interactions of T cells with the environment. The expression patterns of these migration receptors (MR) dictate the tissues into which the effector T cells migrate and enable them to occupy specific niches within the tissue. While MR have been considered primarily to facilitate cell movement, we highlight how the heterogeneity of signaling through these receptors influences the function and fate of T cells in situ. We explore what drives MR expression heterogeneity, how this affects migration, and how this impacts T cell effector function and memory formation.

Keywords: T cell; cellular; heterogeneity; immunity; memory; migration; motility; subset.

Figures

Figure 1

Induction of migratory heterogeneity during priming. MR phenotype is impacted by TCR engagement, the level of co-stimulation, and the cytokine milieu (left). MR play a direct role in the formation of the immunological synapse, but TCR signaling subsequently impacts MR expression [panel 1, adapted from Ref. (8)]. Cytoskeletal rearrangements that involve the actin-binding ezrin (ezr), radixin, and moesin (mo) proteins are necessary for TCR signaling complex polarization. The integrin LFA-1 forms a ring surrounding the cSMAC that supports prolonged T cell-DC engagement, while other MR become excluded from the cSMAC. This process is possibly due to differential polarization of ezrin and moesin. Co-stimulatory signaling through molecules also contributes to the migratory heterogeneity of T cells (panel 2). For example, CD28 controls migration through upregulation of OX40, which is instrumental for CXCR5 expression and T cell localization to germinal centers (GC). In addition CD28/TCR signaling activates the PI3K/AKT pathway, which inhibits Foxo1 leading to decreased KLF2 expression. Differential co-stimulation can impact the levels of CD62L, CCR7, and S1P1 and thereby regulate the egress of T cells into the circulation. Cytokines released by DC promote specific transcriptional profiles that introduce further MR heterogeneity (panel 3). DC-derived IL-12 induces expression of the transcription factor T-bet and determines a CD4+ Th1 or CD8+ effector transcriptional program that results in part in the expression of CXCR3 and PSGL-1, which contribute to homing to peripheral sites. Alternatively, induction of the Tfh-associated transcription factor Bcl6 by IL-6 and IL-21 results in the downregulation of PSGL-1 and increased expression of CXCR5, which allows these cells to migrate from the T cell zones in the paracortex into GC.

Figure 2

Induction of tissue-specific MR profile. Expression of distinct MR combinations results in tissue-specific migration. T cells that are primed in gut-associated lymphoid tissues preferentially express functional PSGL-1, α4β7, and CCR9, which support migration through the post capillary venules of the small intestine to enter the lamina propria and intraepithelial compartment (panel 1). CD103-expressing DC impart the intestinal homing signature on T cells during priming by expression of retinoic acid (RA) in response to microbiota-driven toll-like receptor (TLR) signaling. A different program of MR usage is induced during priming of naïve T cells in skin-draining LN (panel 2). T cells in the skin express the cutaneous lymphocyte antigen (CLA), an inducible carbohydrate modification of PSGL-1, CCR4, CCR8, CCR10, α4β1, and LFA-1, which mitigates their migration into the skin. Analogous to intestinal imprinting, CCR10, but not CCR4, expression is regulated by skin-draining DCs that synthesize the vitamin D3 metabolite, 1,25(OH)2D3. 1,25(OH)2D3 suppresses α4β7 and CCR9 expression and RA inhibits CCR4 and CCR10 expression. In addition, CCR8 expression is imprinted by epidermal keratinocytes, although the skin-specific factors that induce CCR8 remain unknown. Evidence for imprinting of T cells in the lung is limited, but recent evidence suggests that lung DC-activated T cell migrate more efficiently into the lung, which was attributed to CCR4, although other MR are likely to contribute (panel 3). Many lymphocytes in the lung express high levels of α4β1, α1β1, and LFA-1 and CD8+ T cells primed in the mediastinal LN are enriched for CCR5 and CXCR3 expression, suggesting a pulmonary profile driven by distinct molecular mechanisms.