Elsevier

Immunobiology

Volume 218, Issue 2, February 2013, Pages 152-158
Immunobiology

CD226 interaction with CD155 impacts on retention and negative selection of CD8 positive thymocytes as well as T cell differentiation to follicular helper cells in Peyer's Patches

https://doi.org/10.1016/j.imbio.2012.02.010Get rights and content

Abstract

The immunoglobulin-like glycoprotein CD226 represents a receptor activating cytotoxic T and NK cells taking part in tumour surveillance. In addition, CD226 is involved in the differentiation of naïve CD4+ T cells into effector cells. CD155 that is widely over-expressed on tumour cells, was identified as a counter-receptor of CD226 rendering many cancer cells sensitive to NK driven elimination. However, CD155 was also assigned a role in the establishment of follicular helper T cells in the small intestine and the final maturation of CD8 positive thymocytes. Here we show that mice lacking CD226 are distinguished by virtually identical phenotypes as already reported for CD155 deficient mice: a paucity of follicular helper T cells in Peyer's Patches and of terminally matured CD8 T cells in thymus. Moreover, like CD155, CD226 is involved in negative selection of CD8 thymocytes. These observations establish a firm link between the functions of CD155 and CD226 in several T cell differentiation steps.

Introduction

CD155 (poliovirus receptor, PVR) represents an adhesion receptor of the Ig super-family binding in trans to CD226, CD96, nectin-3, vitronectin, and TIGIT/WUCAM (Lange et al., 2001, Bottino et al., 2003, Ikeda et al., 2003, Mueller and Wimmer, 2003, Ravens et al., 2003, Fuchs et al., 2004, Tahara-Hanaoka et al., 2005, Boles et al., 2009, Meyer et al., 2009, Yu et al., 2009). Moreover, human but not mouse CD155 is utilized by poliovirus to infect host cells (Mendelsohn et al., 1989, Bernhardt et al., 1994, Wimmer et al., 1994). CD155 was shown to be involved in the establishment of adherens junctions between epithelial and endothelial cells (Takai et al. 2008) and is implicated in the control of cell motility and proliferation (Ogita et al. 2008). Many tumour cell types were found to over-express CD155 probably exploiting these CD155 functions to escape growth control mechanisms (Masson et al., 2001, Castriconi et al., 2004, Merrill et al., 2004, Sloan et al., 2004, El-Sherbiny et al., 2007, Textor et al., 2008). However, CD155 over-expression renders such cancer cells also more susceptible to killing via cytotoxic T and NK cells expressing CD226 (see below). CD155 deficient mice were established recently (Maier et al., 2007, Abe et al., 2009). The role of CD155 in cell proliferation was corroborated by the finding that mice lacking CD155 are less susceptible to induced development of colitis-associated cancer (Abe et al. 2009). However, the analysis of CD155 deficient mice also revealed hitherto unknown functions of this adhesion receptor in immunology. Thus, CD155 deficient mice show deficits in mounting an isotype switched humoral immune response when antigen was applied orally (Maier et al. 2007). This correlates well with the observation that CD155 deficient animals harbour significantly reduced numbers of follicular helper T cells (TFH) in their intestinal Peyer's Patches (PP) (Seth et al. 2009b). Moreover, CD155 is required to retain terminally matured CD8+ single positive (SP) but not CD4+ SP cells in thymus and also participates in negative selection of CD8+ SP thymocytes (Qiu et al. 2010).

CD226 (DNAX accessory molecule-1, DNAM-1) that is distantly related to CD155 (Du Pasquier et al. 2004), harbours two extra cellular Ig-like domains and is expressed predominantly by NK as well as naïve and antigen experienced T cells (Shibuya et al., 1996, Tahara-Hanaoka et al., 2005, Seth et al., 2009a). CD226 takes part in stimulation of naïve T cells and plays a role in the activation and effector function of Th1 cells (Shibuya et al., 1998, Shibuya et al., 1999, Shibuya et al., 2003, Dardalhon et al., 2005, Shirakawa et al., 2005, Shirakawa et al., 2006). CD226 can associate in cis with LFA-1 and is phosphorylated in its cytoplasmic tail upon cell activation, events that are critically involved in CD226 driven signalling (Shibuya et al., 1998, Shibuya et al., 1999). CD226 was assigned a role in cytotoxic T cell activity and was found to belong to the category of activating NK receptors essential for the elimination of a variety of tumour types (Carlsten et al., 2007, Lakshmikanth et al., 2009, Toutirais et al., 2009) but also dendritic cells (Pende et al., 2006, Seth et al., 2009a). First analyses of mice deficient for CD226 confirmed its involvement in T cell activation and tumour surveillance (Gilfillan et al., 2008, Iguchi-Manaka et al., 2008). Interestingly, it was shown recently that CD226 and CD155 display converse effects in graft-versus-host disease (GVHD). Whereas absence of CD226 gave rise to a significantly milder course of disease (Nabekura et al. 2010), that of CD155 aggravated GVHD (Seth et al. 2011b). Notably, mutations in CD226 were also found to be associated with an increased risk for the development of autoimmune diseases such as type I diabetes or rheumatoid arthritis (Hafler et al., 2009, Maier and Hafler, 2009).

Whereas several reports document the importance of the CD155/CD226-interaction in the elimination of target cells by NK and cytotoxic T cells (Castriconi et al., 2004, Pende et al., 2005b, Tahara-Hanaoka et al., 2006, Chan et al., 2010), it remains elusive which association partner of CD155 is engaged for establishing a regular pool of TFH in PP and proper final maturation of CD8 thymocytes. Here we provide evidence that a functional CD155/CD226-interaction is essential to accomplish this since CD226 deficient mice display largely overlapping phenotypes to those observed in mice lacking CD155: paucity of TFH numbers in PP and of terminally matured CD8 SP in thymus.

Section snippets

Mice

Wild type (WT) BALB/c and BALB/c-CD226tm1Shib mice (CD226−/− mice) were bred in the animal facility of Hannover Medical School. BALB/c-Pvrtm1Gbn mice were described before and are referred to as CD155−/− mice throughout the manuscript (Qiu et al. 2010). CD155−/−CD226−/− double deficient mice were obtained by interbreeding and BALB/c-CD226tm1Shib and BALB/c-Pvrtm1Gbn mice. Genotyping of the F2 generation to obtain homozygous double knock-out breeder pairs was done as described (Maier et al., 2007

CD226 deficiency causes a paucity of TFH cell numbers in PP

The establishment and first analyses of mice deficient for CD226 has been reported recently (Gilfillan et al., 2008, Iguchi-Manaka et al., 2008). In this study, it was intended to refine the investigation of CD226−/− animals with particular emphasis on those cells and organs that were affected in mice lacking the CD226 counter-receptor CD155 (Seth et al., 2009b, Qiu et al., 2010).

In a first set of experiments, the appearance of NK and T cells in spleen, mesenteric lymph node (MLN), and PP of

Discussion

When analyzing BALB/c CD226−/− mice we noted an obvious parallelism of phenotypes that develop in these mice compared to those lacking CD155. Regarding TFH cells in the PP this was surprising. We had shown before that TFH cells isolated from PP are distinguished by a heterogeneous CD226 expression profile (Seth et al. 2009b). Whereas naïve CD4+ T cells uniformly express CD226, TFH cells are distinguished by a very heterogeneous expression pattern. Moreover, TFH cells that arrived in their final

Conflict of interest

The authors declare no competing financial interests.

Acknowledgments

This work was supported by grants BE1886/2-1/-2 to G. Bernhardt from the Deutsche Forschungsgemeinschaft. Q. Qiu and S. Danisch were supported by the Wilhelm Hirte Foundation.

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