Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Alpha E Integrin

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_168

Synonyms

Historical Background

CD103 (integrin αEβ7) was first identified through the binding of a monoclonal antibody (HML-1, human mucosal lymphocyte antigne-1) to a population of lymphocytes that is preferentially associated with gut epithelium (Cerf-Bensussan et al. 1987). It was later identified that HML-1 bound to CD103 which was expressed predominantly on CD3+ CD8+ T cells, and the vast majority of these cells were found in the intestinal mucosa (Russell et al. 1994). Several functionally distinct epitopes were identified. The HML-1 and αE7-1 epitopes were found to function as costimulatory molecules in lymphocyte proliferative responses to a breast cancer epithelial cell line while the αE7-2 and αE7-3 epitopes did not provide such costimulation (Russell et al. 1994).

It is now clear that CD103 is a classic integrin heterodimer composed of the β7 and αE integrin (CD103) subunits. As described above, early studies identified CD103 as an adhesion molecule expressed exclusively by CD8+ T cells in the gut mucosa; however, subsequent studies revealed that CD103 is also expressed by peripheral CD8+ T cells and diverse leukocyte subsets. Recent studies indicate that CD103 is promiscuously expressed by different leukocyte subsets with known immune functional capabilities including not only CD8+ T cells but also interstitial dendritic cells and regulatory T cells. This review is focused on the mechanisms by which CD103 expression is regulated by these leukocye subsets, and the functional impact of CD103 expression on CD8+ T cells, dendritic cells, and regulatory T cells (Tregs). The therapeutic potential of CD103 blockade is also discussed.

Regulation of CD103 Expression

The precise mechanisms regulating CD103 expression by the different leukocyte subsets remain poorly defined. A leading hypothesis is that leukocytes expressing the CD49d/β7 integrin (i.e., gut homing CD8+ T cells) downregulate CD49d and upregulate CD103 in the presence of bioactive transfoming growth factor beta (TGF-β) to generate CD103 expressing cells. There is also evidence that TGF-β directly induces transcription of the αE gene (Itgae) (Robinson et al. 2001). Regardless of the mechanisms involved, it has been clear that bioactive TGF-β plays a dominant role in regulating CD103 expression since the initial reports on the subject by Kilshaw and Murant nearly 20 years ago (Kilshaw and Murant 1990). A key role for TGF-β in regulating CD103 expression by non-CD8 cells is supported by the observation that conversion of naive T cells into CD4+ CD25+ T regs is dependent on TGF-β activity (Coombes et al. 2007). Similarly, TGF-β induces CD103 expression on CD8 T effectors elicited to allogeneic spleen cells cocultured with TGF-β, and CD103 expression by CD8+ T effectors elicited to allogeneic epithelial cells is blocked by TGF-β neutralizing antibody (Hadley et al. 1997). That TGF-β plays a similar role in vivo is supported by the studies of El-Asady et al. who showed that alloreactive CD8+ T cells deficient in the ability to respond to TGF-β were unable to upregulate CD103 in a murine model of GVHD (El-Asady et al. 2005). Studies from the tumor immunology field reveal that TGF-β has a profound impact on the capacity of CD8+ T cells to upregulate CD103 expression following reexposure to cognate antigen (Le Floc’h et al. 2007). Thus, while the precise mechansims likely differ among cell types, the existing data on the subject indicate that TGF-β plays a key role in the process. In this regard, it is important to note that bioactive TGF-β is ubiquitous at sites of inflammation due to its role in wound healing processes, suggesting that the overall impact of this poorly characterized cytokine may promote rather than down modulate immune responses as is often tacitly assumed.

CD103+ CD8+ T Cells

The majority of studies characterizing CD103 expression by CD8+ T cells initially focused on its role as a homing molecule for lymphocytes in the mucosal immune system. Indeed, the elegant studies of Cepek et al. established that CD103 recognizes the epithelial-specific ligand, E-cadherin (Cepek et al. 1994), which is highly expressed on gut epithelial layers. However, there is compelling evidence that CD103/E-cadherin interactions also play a key role in promoting the effector function of peripheral CD8 T effector populations. In vitro studies indicate that CD103 is upregulated on alloreactive CD8+ T cells cocultured with allogeneic renal epithelial cells, and that such expression promotes lytic activity to epithelial cell targets (Hadley et al. 1997). Wang et al. showed that CD8+ T cells do not express CD103 at early timepoints following renal transplant; however, CD8+ T cells in the graft acquire CD103 expression over time (Wang et al. 2004). Interestingly, in a vascularized renal transplant model, kidneys rejected before CD103 expression was acquired. If acute rejection was delayed using cyclosporin, CD8+ T cells gained expression of CD103 and promoted long-term renal injury (Yuan et al. 2005). Studies from the tumor immunology field indicate that CD103 also plays an important role in effective lysis of tumor cells expressing E-cadherin. Le Floc’h et al. found that CD103 was required for tumor lysis of E-cadherin expressing tumor cells, and that the CD103/E-cadherin interaction is required for cytotoxic granule localization to the immunological synapse and exocytosis (Le Floc’h et al. 2007). Importantly, however, it is important to recognize that CD8+ T effectors generally express high levels of CD49d/CD18 (leukocyte function-associated antigen-1, LFA-1), and that interaction of this integrin with its ligand CD54 (intercellular adhesion molecule-1, ICAM-1) plays a dominant role in regulating lytic activity with interaction of CD103 with E-cadherin apparently serving a backup role in providing the requisite signaling pathways in the event that CD54 is down modulated or otherwise not present on the target cell. In humans, CD103 expression by peripheral CD8+ T cells is confined to small subset (<1%) of circulating memory-phenotype cells. In mice, CD103 is expressed at low levels by 40–60% of peripheral CD8+ T cells, the exact frequency of which is strain-dependent.

CD103+ Dendritic Cells

Dendritic cells (DCs) are a highly heterogeneous cell type requiring numerous molecules to classify each of a variety of subsets. CD103+ DCs have been described as involved in generating gut homing T cells and Tregs (Coombes et al. 2007; Jaensson et al. 2008). CD103+ DCs are found in the spleen, skin, lung, and gut-associated lymphoid tissue (GALT). Because the lung and the GALT are in contact with many nonpathogenic antigens, it is likely that the microenvironments of the lung and GALT promote an immunomodulatory phenotype to prevent excess nonspecific inflammatory responses. CD103+ DCs are ideally suited for this purpose. There is evidence that GALT-derived CD103+ DCs produce lower levels of anti-inflammatory cytokines when cocultured with TLR agonists, have increased costimulatory molecule expression, and are less efficient phagocytes than their CD103− counterparts (Coombes et al. 2007; del Rio et al. 2010). CD103+ DCs in the lung display similar functional characteristics (del Rio et al. 2010). Moreover, there is evidence that CD103+ DCs induce Treg formation in the presence of TGF-β and retenoic acid (Coombes et al. 2007). Naive T cells that are activated in the gut by CD103+ DCs acquire the expression of the transcription factor forkhead box protein 3 (FoxP3). In addition to a critical role in inducing Tregs, CD103+ DCs play an important role in generating gut homing CD8+ T cells. CD8+ T cells primed by CD103+ DCs have increased CCR9 and CD49d/β7 expression as compared to CD8+ T cells primed by CD103- DC (Johansson-Lindbom et al. 2005). Lamina propria–derived DCs express higher levels of CD103 than do mesenteric lymph node–derived DCs. Consequently, lamina propria DCs are more potent than mesenteric lymph node DCs in generating gut tropic CD8+ T cells. Although CD103− and CD103+ mesenteric lymph node DCs both activate CD8+ T cells capable of producing interferon gamma, only CD103+ DCs generate gut tropic CD8+ T cells. This phenomenon does not appear to be a product of the gut microenvironment, but rather DC imprinting that occurs prior to DC localization to the gut (Johansson-Lindbom et al. 2005). It is important to note that depletion of CD103-expressing DCs does not compromise host immune responses (Zhang et al. 2009), calling into question the importance of CD103+ DCs in promoting overall immune responses.

CD103+ Tregs

Tregs define an immunomodulatory T cell subset characterized by the capacity to suppress immune responses. There are two populations of CD4+ CD25+ Tregs: natural and adaptive. Natural Tregs are generated in the thymus, while adaptive Tregs are derived in the periphery (Sakaguchi 2005). CD103 is a marker found on a subset of adaptive Tregs (Huehn et al. 2004). It has been shown that CD103+ Tregs have immunosuppressive properties that are equal to, or greater than those of CD103− Tregs. Typically, Tregs are CD4 + CD25+ and express FoxP3; however, there is a population of CD25-CD103+ Tregs that express CTLA-4, suppress T cell proliferation in vitro, and prevent severe colitis in the SCID mouse (Lehmann et al. 2002). There is also a distinct cytokine profile expressed in CD103+ CD25+ Tregs. CD103-CD25+ Tregs secrete levels of IL-4, IL-5, and IL-13 that are similar to Th2 CD4+ T cells, but there is almost no IL-4, IL-5, or IL-13 produced by CD103 + CD25+ Tregs (Lehmann et al. 2002). CD103+ Tregs are also more potent suppressors of T cell proliferation. CD103+ Tregs almost completely prevented naive CD4+ T cell proliferation when nonspecifically stimulated. CD103− Tregs also suppressed proliferation, but to a lesser extent (Lehmann et al. 2002). CD4+ CD25+ CD103+ Tregs also exhibit immunosuppressive properties in vivo. Ongoing chronic graft versus host disease (GVHD) can be suppressed through an in vivo transfer of CD4+ CD25+ CD103+ Tregs. Infusion of CD4+ CD25+ CD103+ Tregs has been shown to reduce the number of alloantibody producing plasma cells in mice with chronic GVHD as well as reduce the number of pathogenic effector T cells in GVHD target organs (Zhao et al. 2008). Moreover, infusion of CD103+ Tregs resulted in twofold lower levels of alloantibody as compared to in vitro activated natural Tregs. Additionally, CD103 defines a population of CD8+ Tregs. CD8+ Tregs can acquire their antigen specificity peripherally and promote systemic tolerance. Injection into the anterior chamber of the eye will generate CD8+ Tregs specific for the injected antigen. CD103 has been shown to be essential for the development and function of the CD8+ Tregs (Keino et al. 2006). Koch et al. characterize CD103+ CD8+ Tregs as phenotypically different from other CD8+ suppressor T cell populations. CD103+ CD8+ Tregs express CD28, but lack FoxP3, CD25, LAG-3, CTLA-4, and GITR (Koch et al. 2008).

Therapeutic Potential of CD103 Blockade

The utility of therapeutic strategies for targeting the CD103 pathway are clouded by promiscuity in CD103 expression and uncertainty regarding its precise function on different cell types. CD103 is regulated by TGF-β, but the activation state of the CD8+ T cells at the time it encounters TGF-β determines the function of the CD8+ T cell (Hadley et al. 1997); consequently TGF-β is not a viable therapeutic target. Targeted disruption of CD103 on CD8 effector T cells prevents intestinal GVHD and prolongs renal allograft survival (El-Asady et al. 2005; Yuan et al. 2005), suggesting that CD103 itself may be the optimal therapeutic target. However, CD103+ Tregs have been shown to ameliorate chronic GVHD (Zhao et al. 2008), and CD103+ DC have been shown to promote Treg development (Coombes et al. 2007), arguing against the therapeutic poential of CD103 blockade. Depletion of CD103-expressing cells in vivo dramatically attenuates CD8+ T cell responses, arguing that CD103+ DC or Tregs do not serve critical immune functions in all immune responses (Zhang et al. 2009). Consequently, the overall role of CD103 in promoting disease remains controversial, and this ambiguity has hindered the development of therapeutic agents to target the pathway.

Summary

CD103 is a classic integrin heterodimer composed of the β7 and αE integrin (CD103) subunits that recognizes the epithelial cell-specific ligand, E-cadherin. CD103 is expressed by diverse leukocyte populations, and there is increasing evidence that it plays a key role in both promoting and regulating immune responses. Whether or not CD103 provides a viable therapeutic target remains to be determined.

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© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of SurgeryThe Ohio State University Medical CenterColumbusUSA