Tissue-Resident Memory T Cells

“Much like naive T cells, Tcm cells patrol secondary lymphoid organs (SLOs), which include lymph nodes (LNs) and the white pulp (WP) of spleen (Figure 1) (von Andrian and Mackay, 2000; Sallusto et al., 1999).”

“Tem cells also lack LN homing receptors (CD62L and CCR7), yet expressed distinct patterns of other homing receptors, and on that basis it was proposed that Tem cells recirculate between blood and nonlymphoid tissues (NLTs) or remain poised to mobilize to sites of inflammation (Butcher and Picker, 1996; Mackay et al.,…”

“S1PR1 downregulation is concomitantly associated with cell surface expression of the C-type lectin CD69 (Cyster and Schwab, 2012; Matloubian et al., 2004; Schober et al., 1999; Shiow et al., 2006; Skon et al., 2013).”

“Additionally, CD62L cells isolated fromblood and spleen did not recapitulate the panoply of phenotypes expressed by memory T cells isolated from the small intestinal mucosa, lung, and brain (Hawke et al., 1998; Hogan et al., 2001; Kim et al., 1998; Masopust et al., 2001a; van der Most et al., 2003).”

“Naive T cells enter SLOs from blood using a combination of selectins, chemokines, and integrins, and then patrol for 12– 24 hr before leaving to explore other SLOs in their continuous quest for cognate Ag (von Andrian and Mackay, 2000; von Andrian and Mempel, 2003).”

“Similarly, dendritic cells upregulate CCR7 after activation in tissues, which then acts in concert with S1PR1 to promote migration to downstream SLOs (Braun et al., 2011; Czeloth et al., 2005; Lamana et al., 2011; Ohl et al., 2004; Saeki et al., 1999).”

“S1PR1 downregulation is concomitantly associated with cell surface expression of the C-type lectin CD69 (Cyster and Schwab, 2012; Matloubian et al., 2004; Schober et al., 1999; Shiow et al., 2006; Skon et al., 2013).”

“One interpretation is that aeb7 allows CD8+ T cells to physically adhere to E-cadherin expressed on epithelial cells.”

“It was found that only effector, and notmemory, CD8+ T cells were competent to enter the small intestine, brain, or salivary gland (Hickey et al., 1991; Hofmann and Pircher, 2011; Masopust et al., 2010; Wakim et al., 2010).”

“However, NLT-derived memory T cells also express many markers not shared by any circulating population of memory T cells within blood (Casey et al., 2012; Gebhardt et al., 2009; Hawke et al., 1998; Hofmann and Pircher, 2011; Jiang et al., 2012; Masopust et al., 2006; Ray et al., 2004).”

“Similarly, dendritic cells upregulate CCR7 after activation in tissues, which then acts in concert with S1PR1 to promote migration to downstream SLOs (Braun et al., 2011; Czeloth et al., 2005; Lamana et al., 2011; Ohl et al., 2004; Saeki et al., 1999).”

“For example, the antiviral cytokine IFN-g is critical for clearing L. major, HSV-2, and HBV infections (Guidotti et al., 1996; Iijima et al., 2008; Müller et al., 2012).”

“Memory T cells can be isolated from SLO, blood-borne compartments, and NLTs (Masopust et al., 2001b; Reinhardt et al., 2001; Woodland and Kohlmeier, 2009), and at least for CD8+ T cells, this may include NLTs that were not sites of infection (Hofmann and Pircher, 2011; Kaufman et al., 2008; Liu et…”

“…productively primed within SLOs, they give rise to effector cells that migrate throughout the host and leave behind a memory population that persists long after pathogen clearance (Dutton et al., 1998; Harty and Badovinac, 2008; Lefrançois, 2006; Sallusto et al., 2010; Williams and Bevan, 2007).”

“Unfortunately, there are few long-term studies on the durability of T cell memory in humans, even in blood (Hammarlund et al., 2003; Nanan et al., 2000; Van Epps et al., 2002), and tracking T cell memory in NLTs is less tractable.”

“Although it is uncertain whether this is related to a lack of TGF-bR expression, responsiveness to TGF-b is clearly dependent on T cell differentiation state (Li and Flavell, 2008).”

“Mechanisms of Trm Maintenance In order for Trm cells to be maintained within tissues, they must adapt to local survival cues, resist shedding into the lumen at mucosal epithelial surfaces, and ignore egress signals (Masopust and Schenkel, 2013; Mueller et al., 2013).”

“Shorter-term studies in mice and rhesus macaques revealed that tissue memory CD8+ T cells are relatively stable for 300–700 days (Jiang et al., 2012; Kaufman et al., 2008; Masopust et al., 2001b).”

“S1PR1 mediates T cell egress in lymph nodes by inducing chemotaxis to sphingosine-1-phosphate (S1P) present within efferent lymph (Cyster and Schwab, 2012).”

“In this regard, it will be crucial to determine whether the total number of Trm cells established within NLTs is tightly regulated, as it appears to be for Tcm cells within LNs, or whether it is flexible, as shown for Tem cells (Vezys et al., 2009).”

“When S1PR1 is forcibly expressed on CD8+ T cells, Trm cells are reduced in NLTs (Skon et al., 2013).”

“…of Tg mice or T cells (Bromley et al., 2013; Ugur et al., 2014), tissue grafts (Gebhardt et al., 2009;Masopust et al., 2010), lymphatic canulation (Mackay et al., 1990), transfers of labeled T cells (Hofmann and Pircher, 2011; Masopust et al., 2004; 2010), and/or parabiotic surgery (Iijima and…”

“Parabiosis experiments demonstrated that 1%–5% of memory CD8+ T cells within spleen and LNs are Trm cells after acute LCMV infection (Schenkel et al., 2014a).”

“For instance, a larger number of Trm cells within the female reproductive tract are induced to express aeb7 after local inflammation compared to systemic infection or in the presence of local inflammation (Çuburu et al., 2012; Li et al., 2008; Mackay et al., 2012; Shin and Iwasaki, 2012).”

“…productively primed within SLOs, they give rise to effector cells that migrate throughout the host and leave behind a memory population that persists long after pathogen clearance (Dutton et al., 1998; Harty and Badovinac, 2008; Lefrançois, 2006; Sallusto et al., 2010; Williams and Bevan, 2007).”

“Mechanisms of Trm Maintenance In order for Trm cells to be maintained within tissues, they must adapt to local survival cues, resist shedding into the lumen at mucosal epithelial surfaces, and ignore egress signals (Masopust and Schenkel, 2013; Mueller et al., 2013).”

“…(Gebhardt et al., 2009;Masopust et al., 2010), lymphatic canulation (Mackay et al., 1990), transfers of labeled T cells (Hofmann and Pircher, 2011; Masopust et al., 2004; 2010), and/or parabiotic surgery (Iijima and Iwasaki, 2014; Jiang et al., 2012; Klonowski et al., 2004; Schenkel et al., 2013).”

“Additionally, CD62L cells isolated fromblood and spleen did not recapitulate the panoply of phenotypes expressed by memory T cells isolated from the small intestinal mucosa, lung, and brain (Hawke et al., 1998; Hogan et al., 2001; Kim et al., 1998; Masopust et al., 2001a; van der Most et al., 2003).”

“These discrepancies were partly clarified upon the clear demonstration that populations of memory T cells were settled within many NLTs (Figure 1) (Gebhardt et al., 2009; Jiang et al., 2012; Masopust et al., 2010; Teijaro et al., 2011; Wakim et al., 2010).”

“After acute viral infections in mice and humans, effector T cells transiently upregulate a4b7 integrin, which facilitates migration into the small intestine (Campbell and Butcher, 2002; Liu et al., 2006; Masopust et al., 2010).”

“Similarly, dendritic cells upregulate CCR7 after activation in tissues, which then acts in concert with S1PR1 to promote migration to downstream SLOs (Braun et al., 2011; Czeloth et al., 2005; Lamana et al., 2011; Ohl et al., 2004; Saeki et al., 1999).”

“KLF2 promotes other homing markers involved in recirculation, including CCR7 expression (Carlson et al., 2006), which might promote leukocyte egress fromNLT via CCL19+ andCCL21+ afferent lymphatics.”

“A non-mutually exclusive alternative hypothesis is that aeb7 expression promotes survival of CD8+ T cells, as aeb7+ CD8+ T cells express more of the prosurvival protein Bcl-2 early after infection in the brain and skin epidermis (Mackay et al., 2013; Wakim et al., 2010).”

“…productively primed within SLOs, they give rise to effector cells that migrate throughout the host and leave behind a memory population that persists long after pathogen clearance (Dutton et al., 1998; Harty and Badovinac, 2008; Lefrançois, 2006; Sallusto et al., 2010; Williams and Bevan, 2007).”

“Indeed, CD8+ and CD4+ T cell memory in the lung and lung airways wanes within months after influenza infection, leading to the loss of protective heterosubtypic immunity (Hogan et al., 2001; Liang et al., 1994; Wu et al., 2014).”

“Importantly, Trm cell-dependent activation of parenchymal, innate, and adaptive immunity triggered the induction of a local protective antiviral state (Ariotti et al., 2014; Schenkel et al., 2014b).”

“In the brains of Toxoplasma gondii-infected mice, CXCL10 expression increases the speed of local CD8 T cells (Harris et al., 2012).”

“Elegant work demonstrated paradoxically that CCR7 expression by T cells might be required for egress from NLT (Bromley et al., 2005; Debes et al., 2005).”

“After acute viral infections in mice and humans, effector T cells transiently upregulate a4b7 integrin, which facilitates migration into the small intestine (Campbell and Butcher, 2002; Liu et al., 2006; Masopust et al., 2010).”

“Elegant work demonstrated paradoxically that CCR7 expression by T cells might be required for egress from NLT (Bromley et al., 2005; Debes et al., 2005).”

“S1P is also produced by afferent lymphatic endothelial cells draining NLTs and is important for mature dendritic cells to migrate to tissue-draining lymph nodes (Czeloth et al., 2005; Lamana et al., 2011; Maeda et al., 2007; Pham et al., 2010).”

“Memory T cells can be isolated from SLO, blood-borne compartments, and NLTs (Masopust et al., 2001b; Reinhardt et al., 2001; Woodland and Kohlmeier, 2009), and at least for CD8+ T cells, this may include NLTs that were not sites of infection (Hofmann and Pircher, 2011; Kaufman et al., 2008; Liu et…”

“For instance, aggregates generated in the vagina of HSV-2-infected mice are composed mostly ofmacrophages andCD4+ T cells, whereas aggregates that form in the brain after local vesicular stomatitis virus infection are composed of CD8+ T cells and CD103+ DCs (Iijima and Iwasaki, 2014; Wakim et al., 2010).”

“Indeed, CD8+ and CD4+ T cell memory in the lung and lung airways wanes within months after influenza infection, leading to the loss of protective heterosubtypic immunity (Hogan et al., 2001; Liang et al., 1994; Wu et al., 2014).”

“In human cadavers, it was recently shown that 50%–80%of CD4+ andCD8+ T cells express CD69 in spleen and LNs (Sathaliyawala et al., 2013) and CD69+ CD8+ T cells included those with defined specificity for CMV and influenza (Turner et al., 2014).”

“Indeed, CD8+ and CD4+ T cell memory in the lung and lung airways wanes within months after influenza infection, leading to the loss of protective heterosubtypic immunity (Hogan et al., 2001; Liang et al., 1994; Wu et al., 2014).”

“Rather than killing these infected neurons and causing immunopathology, granzyme B degrades the immediate early protein ICP4, which is important for viral replication (Knickelbein et al., 2008).”

“TLOs (Neyt et al., 2012) and leukocyte aggregates (TLOs have HEVs, whereas leukocyte aggregates do not) have long been noted within NLTs. Historically, they have occasionally been referred to as ectopic lymphoid structures, or abnormal sites of inflammation.”

“Interestingly, E-cadherin is also expressed by memory CD8 T cells isolated from the salivary gland, small intestine epithelium, lung, skin, thymus, and brain and might contribute to maintenance via homophilic E-cadherin interactions between Trm cells and epithelial cells (Hofmann and Pircher, 2011; Mackay et al., 2013…”

“After oral infection with Listeria monocytogenes, aeb7 is important for the accumulation of CD8+ T cells in the small intestine epithelium but is dispensable for long-term maintenance (Sheridan et al., 2014).”

“Although more abundant during infection (Cromwell et al., 2011; Kobayashi et al., 2002;; Zhu et al., 2009), they are present in healthy humans and to a lesser degree in SPF mice, which have comparatively little infectious history.”

“In this regard, it will be crucial to determine whether the total number of Trm cells established within NLTs is tightly regulated, as it appears to be for Tcm cells within LNs, or whether it is flexible, as shown for Tem cells (Vezys et al., 2009).”

“Similarly, dendritic cells upregulate CCR7 after activation in tissues, which then acts in concert with S1PR1 to promote migration to downstream SLOs (Braun et al., 2011; Czeloth et al., 2005; Lamana et al., 2011; Ohl et al., 2004; Saeki et al., 1999).”

“Exiting SLOs is an active process and depends on gradual T cell sensitization to sphingosine-1 phosphate receptor 1 (S1PR1)-dependent chemotactic gradients (Arnon et al., 2011; Lo et al., 2005; Shannon et al., 2012).”

“In fact, within lung, intravascular NKT cells precipitate allergies (Scanlon et al., 2011) and intravascular CD4 T cells produce IFN-g in vivo in response to mTB (Sakai et al., 2014).”

“For instance, the integrin a1b1 binds laminins and collagens and is highly expressed on CD8+ Trm in the brain, small intestine, lung, and skin (Gebhardt et al., 2009; Mackay et al., 2013; Ray et al., 2004; Wakim et al., 2012).”

“Following acute intraperitoneal LCMV challenge, up to 95% of memory CD8 T cells isolated from perfused lung were derived from vasculature (Anderson et al., 2012).”

“…and NLTs (Masopust et al., 2001b; Reinhardt et al., 2001; Woodland and Kohlmeier, 2009), and at least for CD8+ T cells, this may include NLTs that were not sites of infection (Hofmann and Pircher, 2011; Kaufman et al., 2008; Liu et al., 2006; Masopust et al., 2010; 2004; Zhu et al., 2012).”

“Additionally, CD8 Trm cells in the epidermis are able to adopt a ‘‘dendriticlike’’ morphology, allowing them to scan multiple host cells at once for pathogen and thus maximizing their ability to locate infected cells (Ariotti et al., 2012; Gebhardt et al., 2011).”

“Similarly, it has been demonstrated that T cells infiltrating the TGF-b rich microenvironment of tumors also express aeb7 (Le Floc’h et al., 2007).”

“However, these yieldsmight underestimate the number of lymphocytes in NLTs (Ganusov and De Boer, 2007; Selby et al., 1984).”

“After murine lung infections associated with depots of residual antigen, there is evidence for retention of CD8 T cells within draining mediastinal LNs, and CD69 and CD103 are expressed in these contexts (Takamura et al., 2010; Zammit et al., 2006).”

“CD8+ Trm cells exhibited biased distribution to splenic marginal zone and LN sinuses (Schenkel et al., 2014a), which often represent the initial sites of microbial entry to these organs (Aoshi et al., 2009; Gonzalez et al., 2010; Junt et al., 2007).”

“For example, type I interferon (IFN), interleukin-33 (IL-33), and tumor necrosis factor-a (TNFa) and other cytokines all induce CD69 upregulation on T cells (Casey et al., 2012; Kohlmeier et al., 2010; López-Cabrera et al., 1995; Skon et al., 2013).”

“T cell reactivation within these LN barrier sites precipitates rapid detection, innate immune activation, and recruitment of CXCR3+ memory T cells, all of which likely contribute to accelerating pathogen control (Kastenmüller et al., 2013; Sung et al., 2012).”

“Active TGF-b is constitutively available at many epithelial surfaces, including skin epidermis and small intestine epithelium (Koyama and Podolsky, 1989; Yang et al., 1999).”

“In this regard, it will be crucial to determine whether the total number of Trm cells established within NLTs is tightly regulated, as it appears to be for Tcm cells within LNs, or whether it is flexible, as shown for Tem cells (Vezys et al., 2009).”

“A network of natural killer (NK) cells, gd T cells, and innate-like CD8+ T cells are also prepositioned near lymph node sinuses, and when activated, prevent systemic pathogen dissemination (Kastenmüller et al., 2012; Sheridan et al., 2013).”

“Leukocyte aggregates have been characterized in the brain, salivary gland, lung, female reproductive tract, skin, and liver under a variety of infectious or inflammatory conditions (Anderson et al., 2014; Huang et al., 2013; Iijima and Iwasaki, 2014; Natsuaki et al., 2014; Stahl et al., 2013; Wakim et al., 2010; Walto…”

“Parabiosis experiments demonstrated that 1%–5% of memory CD8+ T cells within spleen and LNs are Trm cells after acute LCMV infection (Schenkel et al., 2014a).”

“Taken together, it appears that localization to certain NLTs is sufficient to drive adoption of specific phenotypes, much like inductive cues that drivemonocyte differentiation in the small intestine (Zigmond and Jung, 2013).”

“KLRG1+ effectors are also particularly vulnerable to apoptosis when treated with TGF-b in vitro (Sanjabi et al., 2009).”

“Similarly, dendritic cells upregulate CCR7 after activation in tissues, which then acts in concert with S1PR1 to promote migration to downstream SLOs (Braun et al., 2011; Czeloth et al., 2005; Lamana et al., 2011; Ohl et al., 2004; Saeki et al., 1999).”

“It was not demonstrated in these studies whether recirculating memory T cells migrate to tissues to replenish Trm cells, which has been proposed for lung airways (Ely et al., 2006), or whether Trm cells were self-sustaining.”

“, 2001; Woodland and Kohlmeier, 2009), and at least for CD8 T cells, this may include NLTs that were not sites of infection (Hofmann and Pircher, 2011; Kaufman et al., 2008; Liu et al., 2006; Masopust et al., 2010; 2004; Zhu et al., 2012).”

“In animal models, this issue can be simply addressed using in vivo intravascular-staining strategies (Galkina et al., 2005; Muppidi et al., 2011; Scanlon et al., 2011), which abrogate the need to perfuse.”

“Indeed, CD8 and CD4 T cell memory in the lung and lung airways wanes within months after influenza infection, leading to the loss of protective heterosubtypic immunity (Hogan et al., 2001; Liang et al., 1994; Wu et al., 2014).”

“Moreover, NLT populations might be particularly prone to death during lengthy or harsh processing procedures, because they do not survive well in culture (Brunner et al., 2001; Wakim et al., 2012).”

“Blocking integrin av results in increased parasite burden during local Leishmania major infection, suggesting that increased T cell motility is in important for pathogen control (Overstreet et al., 2013).”

“…productively primed within SLOs, they give rise to effector cells that migrate throughout the host and leave behind a memory population that persists long after pathogen clearance (Dutton et al., 1998; Harty and Badovinac, 2008; Lefrançois, 2006; Sallusto et al., 2010; Williams and Bevan, 2007).”

“For example, the antiviral cytokine IFN-g is critical for clearing L. major, HSV-2, and HBV infections (Guidotti et al., 1996; Iijima et al., 2008; Müller et al., 2012).”

“S1P is also produced by afferent lymphatic endothelial cells draining NLTs and is important for mature dendritic cells to migrate to tissue-draining lymph nodes (Czeloth et al., 2005; Lamana et al., 2011; Maeda et al., 2007; Pham et al., 2010).”

“S1PR1 downregulation is concomitantly associated with cell surface expression of the C-type lectin CD69 (Cyster and Schwab, 2012; Matloubian et al., 2004; Schober et al., 1999; Shiow et al., 2006; Skon et al., 2013).”

“Additionally, IFN-g effects are not limited to infected host cells that T cells contact directly, but can also act on neighboring infected host cells (Müller et al., 2012).”

“After acute viral infections in mice and humans, effector T cells transiently upregulate a4b7 integrin, which facilitates migration into the small intestine (Campbell and Butcher, 2002; Liu et al., 2006; Masopust et al., 2010).”

“Unfortunately, there are few long-term studies on the durability of T cell memory in humans, even in blood (Hammarlund et al., 2003; Nanan et al., 2000; Van Epps et al., 2002), and tracking T cell memory in NLTs is less tractable.”

“For example, type I interferon (IFN), interleukin-33 (IL-33), and tumor necrosis factor-a (TNFa) and other cytokines all induce CD69 upregulation on T cells (Casey et al., 2012; Kohlmeier et al., 2010; López-Cabrera et al., 1995; Skon et al., 2013).”

“Memory CD8 T cells in certain NLT maintain constitutive granzyme B expression and like recently activated effectors, mediate ex vivo cytotoxicity (Kim et al., 1998; Masopust et al., 2006).”

“Active TGF-b is constitutively available at many epithelial surfaces, including skin epidermis and small intestine epithelium (Koyama and Podolsky, 1989; Yang et al., 1999).”

“However, NLT-derived memory T cells also express many markers not shared by any circulating population of memory T cells within blood (Casey et al., 2012; Gebhardt et al., 2009; Hawke et al., 1998; Hofmann and Pircher, 2011; Jiang et al., 2012; Masopust et al., 2006; Ray et al., 2004).”

“Work from James Hogg prognosticated this important technical issue when he reported that the ratio of neutrophils to RBCs was 100-fold higher in lung capillaries than in large-bore blood vessels (Hogg et al., 1994).”

“This issue extends to lymphocytes as well (which have a 3-fold greater volume than RBCs; 90 femtoliters versus 290 femtoliters (Segel et al., 1981)).”

“…in the brain, salivary gland, lung, female reproductive tract, skin, and liver under a variety of infectious or inflammatory conditions (Anderson et al., 2014; Huang et al., 2013; Iijima and Iwasaki, 2014; Natsuaki et al., 2014; Stahl et al., 2013; Wakim et al., 2010; Walton et al., 2011).”

“After murine lung infections associated with depots of residual antigen, there is evidence for retention of CD8+ T cells within draining mediastinal LNs, and CD69 and CD103 are expressed in these contexts (Takamura et al., 2010; Zammit et al., 2006).”

“In animal models, this issue can be simply addressed using in vivo intravascular-staining strategies (Galkina et al., 2005; Muppidi et al., 2011; Scanlon et al., 2011), which abrogate the need to perfuse.”

“The cytokine mechanism(s) controlling KLF2 and the S1PR1CD69 axis in NLTs is less well understood.”

“CD8+ Trm cells exhibited biased distribution to splenic marginal zone and LN sinuses (Schenkel et al., 2014a), which often represent the initial sites of microbial entry to these organs (Aoshi et al., 2009; Gonzalez et al., 2010; Junt et al., 2007).”

“Because these signatures are also constitutively expressed by T cells within the intestinal mucosa, it was originally proposed that mucosal T cells represented activated effectors (Montufar-Solis et al., 2007).”

“For instance, a larger number of Trm cells within the female reproductive tract are induced to express aeb7 after local inflammation compared to systemic infection or in the presence of local inflammation (Çuburu et al., 2012; Li et al., 2008; Mackay et al., 2012; Shin and Iwasaki, 2012).”

“Similarly, dendritic cells upregulate CCR7 after activation in tissues, which then acts in concert with S1PR1 to promote migration to downstream SLOs (Braun et al., 2011; Czeloth et al., 2005; Lamana et al., 2011; Ohl et al., 2004; Saeki et al., 1999).”

“Vascular contamination by CD4 T cells is less than CD8 T cells in models addressed thus far (Anderson et al., 2014; Knudson et al., 2014; Teijaro et al., 2011) but is still significant.”

“Unfortunately, there are few long-term studies on the durability of T cell memory in humans, even in blood (Hammarlund et al., 2003; Nanan et al., 2000; Van Epps et al., 2002), and tracking T cell memory in NLTs is less tractable.”

“Additionally, CD62L cells isolated fromblood and spleen did not recapitulate the panoply of phenotypes expressed by memory T cells isolated from the small intestinal mucosa, lung, and brain (Hawke et al., 1998; Hogan et al., 2001; Kim et al., 1998; Masopust et al., 2001a; van der Most et al., 2003).”

“Moreover, NLT populations might be particularly prone to death during lengthy or harsh processing procedures, because they do not survive well in culture (Brunner et al., 2001; Wakim et al., 2012).”

“transiently reduce expression of the transcription factor kruppellike factor 2 (KLF2), a positive regulator of S1PR1 transcription (Preston et al., 2013; Skon et al., 2013; Grayson et al., 2001).”

“…in the brain, salivary gland, lung, female reproductive tract, skin, and liver under a variety of infectious or inflammatory conditions (Anderson et al., 2014; Huang et al., 2013; Iijima and Iwasaki, 2014; Natsuaki et al., 2014; Stahl et al., 2013; Wakim et al., 2010; Walton et al., 2011).”

“Although more abundant during infection (Cromwell et al., 2011; Kobayashi et al., 2002;; Zhu et al., 2009), they are present in healthy humans and to a lesser degree in SPF mice, which have comparatively little infectious history.”

“Exiting SLOs is an active process and depends on gradual T cell sensitization to sphingosine-1 phosphate receptor 1 (S1PR1)-dependent chemotactic gradients (Arnon et al., 2011; Lo et al., 2005; Shannon et al., 2012).”

“Although more abundant during infection (Cromwell et al., 2011; Kobayashi et al., 2002;; Zhu et al., 2009), they are present in healthy humans and to a lesser degree in SPF mice, which have comparatively little infectious history.”