Influence of the Route of Infection on Development of T-Cell Receptor β-Chain Repertoires of Reovirus-Specific Cytotoxic T Lymphocytes

Abstract

It is well established that the route of infection affectsRespiratory enteric orphan virus (reovirus) has been used as a model viral pathogen to study virus-host interactions at mucosal surfaces and in the periphery. Reovirus is a nonenveloped, segmented double-stranded RNA virus (31) that replicates and elicits both humoral and cell-mediated immunity following oral or parenteral infection (7,13,14,16,25). After gaining access to the intestinal tissue via the M cells of the Peyer's patches (PP) (46), reovirus serotype 1 strain Lang (T1/L) infection of immunocompetent mice causes a self-limited disease of enterocytes of the crypts of Lieberkuhn adjacent to the PP of the distal ileum (37). In response, virus-specific cytotoxic T lymphocytes (CTLs) are induced within the PP (25). CTLs migrate via efferent lymphatic vessels to the mesenteric lymph nodes and then through the thoracic duct lymph and the systemic circulation to the spleen (25) or to intestinal mucosal sites, such as the intestinal intraepithelial lymphocyte (IEL) compartment (8, 9, 24). Parenteral infection with reovirus induces virus-specific CTLs in the draining peripheral lymph nodes and spleen (22,45).Although the humoral immune response to reovirus is influenced by microenvironmental or cellular factors at the anatomic site of infection (7,26,44), it is not known whether intestinal reovirus infection results in a CTL response distinct from that following parenteral infection. Most reovirus-specific CTLs are CD8␣␤ϩ TCR␣␤ ϩ Thy-1 ϩ and major histocompatibility complex (MHC) class I restricted (25). In addition, reovirus-specific CD8 ϩ CTLs induced in the PP following enteric infection and in the lung following respiratory infection express the unusual cell surface marker called germinal center and T antigen (23,44). Intratracheal instillation of reovirus elicits an unusual population of cytotoxic CD4 ϩ CD8␣␤ ϩ TCR␣␤ ϩ T cells (34), suggesting that unique CTL populations might be induced by infection at distinct anatomic locations. Furthermore, enteric reovirus T1/L infection of C3H mice has been shown to elicit CD8␣␤ ϩ CTL populations expressing V␤12 and V␤17, with minor populations expressing V␤2, V␤7, V␤9, and V␤14 among the IELs (8). These CTL populations were thought to be representative of the CTL response primed in the PP following oral infection with reovirus T1/L (9), although some might have been derived in situ, given the uncertain ontogeny of the IEL.There are several reasons why CTLs induced following oral infection could be different from those induced parenterally. During enteric reovirus infection, the ingested virions undergo pancreatic chymotryptic proteolysis of the outer coat proteins in the duodenum to yield infectious intermediate subviral particles (3). This processing within the lumen of the small intestine could potentially generate antigenic determinants distinct from those generated in the systemic periphery. Additionally, cleaved viral antigens might be taken up by intestinal absorptive epithelial cells (32,42), which expr...

Characterization of Homologous and Heterologous Rotavirus-Specific T-Cell Responses in Infant and Adult Mice

“…One possible explanation for this discrepancy might be the different routes of immunization and different antigen formulation used in these studies: intranasal immunization of protein or peptide with LT adjuvant in the study by Choi et al versus oral infection with live virus in our study. It has been recently shown (16) that the route of virus infection can affect the selection and expansion of subpopulations of virus-specific CTLs, and considering our results, this might also be the case for CD4 ϩ T-cell populations. We are currently testing this hypothesis by comparing the RV-specific CD8 ϩ and CD4 ϩ T-cell populations induced after oral, intranasal, and intramuscular immunization with RRV.…”

“…Interestingly, our mapping strategy didn't identify the two class I epitopes mapped by Buesa et al (4), VP7 [5][6][7][8][9][10][11][12][13] and VP7 [8][9][10][11][12][13][14][15][16] , in the C57BL/6 and BALB/c backgrounds, re- …”

Enteric reovirus infection stimulates peanut-specific IgG2a responses in a mouse food allergy model

“…In fact, its presence in water sources is commonly used as a sign of fecal contamination (Abbaszadegan et al, 1993; Fout et al, 2003). Following intestinal infection in mice, reovirus induces stereotypic Th1-driven responses characterized by the development of high titers of virus-specific serum IgG2a antibody (Major and Cuff, 1996), and the induction of interferon-γ- (IFN-γ) producing T-cells (London et al, 1987; Fulton et al, 2004). Reovirus activates intestinal dendritic cells in vivo (Errington et al, 2008; Johansson et al, 2007; Fleeton et al, 2004) and under some circumstances reovirus (Rubin et al, 1981) or its hemagglutinin (Greene and Weiner, 1980) can induce oral tolerance, indicating that the immune response to reovirus in mice has the potential to regulate allergic responses by a variety of mechanisms.…”

Experimental intestinal reovirus infection of mice

“…T CTL Vβ repertoire appears to be skewed in favor of Vβ6, Vβ, 12, and Vβ17, although Vβ2, Vβ7, Vβ9, and Vβ14 also may participate in the response to reovirus [55,56]. Interestingly, the Jβ gene segment of Vβ6 TCR clones expanded in SCID mice showed more restricted Jβ gene usage in orally-infected mice versus systemically-infected animals [55], implying that repertoire selection of anti-reoviral T cells is dictated in part by the route of viral entry.…”

“…T CTL Vβ repertoire appears to be skewed in favor of Vβ6, Vβ, 12, and Vβ17, although Vβ2, Vβ7, Vβ9, and Vβ14 also may participate in the response to reovirus [55,56]. Interestingly, the Jβ gene segment of Vβ6 TCR clones expanded in SCID mice showed more restricted Jβ gene usage in orally-infected mice versus systemically-infected animals [55], implying that repertoire selection of anti-reoviral T cells is dictated in part by the route of viral entry. Using a germinal center/T cell marker (GCT), London and colleagues reported an increase in GCT+, Thy-1+, CD8+ IELs and lamina propria lymphocytes (LPL) bearing CD11c, a marker of T cell activation in the gut [57], in mice infected intraduodenally with serotype 1 reovirus T1L [58].…”