α4β7 independent pathway for CD8+ T cell–mediated intestinal immunity to rotavirus

Kuklin, Nelly A.; Rott, Lusijah S.; Darling, Jama M.; Campbell, James J.; Franco, Manuel; Feng, Ningguo; Müller, Werner; Wagner, Norbert; Altman, John D.; Butcher, Eugene C.; Greenberg, Harry B.

doi:10.1172/jci10927

Cited by 57 publications

(53 citation statements)

References 36 publications

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“…T lymphocytes were derived from peripheral blood of convalescent juvenile macaques with a recent history of rotavirus infection. In rotavirus-infected humans and rodents, both CD4 ϩ and CD8 ϩ T lymphocytes were found to contribute to virus clearance (12,18,24,32). In addition, there is some evidence to suggest that rotavirus VP6 T-helper cell epitopes may be able to form ligands with CD4 ϩ cells derived from different host species (2).…”

Section: Discussionmentioning

confidence: 99%

Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

Sestak

McNeal

Choi

et al. 2004

J Virol

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The appearance of virus-specific CD4؉ and/or CD8 ؉ T lymphocytes in peripheral blood of captive juvenile rhesus macaques (Macaca mulatta) was observed following rotavirus infection. These cell-mediated immune responses were measured following experimental or natural infection after rotavirus was isolated from stool specimens of asymptomatic animals. The virus isolated was a new strain of simian rotavirus that we named TUCH (for Tulane University and Cincinnati Children's Hospital). Restimulation of peripheral T lymphocytes by inactivated double-or triple-layered TUCH rotavirus particles containing either VP6 or VP4 and VP7 on their respective surfaces resulted in increased quantities of interleukin-6 (IL-6) and IL-12 in cell culture supernatants. Recall responses to rotavirus by CD4 ؉ and CD8 ؉ T lymphocytes were associated with accumulation of intracellular IL-6 and gamma interferon. Antigen presentation of TUCH rotavirus to lymphocytes was mediated via differentiated cultures of monocyte-derived dendritic (HLA-DR ؉ ) cells. This is the first report demonstrating cell-mediated immune responses to rotavirus in nonhuman primates. Further exploration of rhesus macaques in vaccine trials with human rotavirus vaccine candidates is the major objective of future studies.In the United States, rotavirus infection of 6-to 36-monthold children results in more than 50,000 hospitalizations each year (41). Throughout the world, at least 500,000 children die annually due to rotavirus-induced dehydration (25,28,41). Although extensive trials of novel vaccine candidates were performed with gnotobiotic piglets or genetically defined mice (28,41,44), none of these candidates have been evaluated in primates. Therefore, development of a nonhuman primate (NHP) model for evaluation of human rotavirus vaccine candidates is urgently needed. Although several NHP species, including chimpanzees and baboons as well as rhesus, vervet, pigtailed, and squirrel monkeys, have been reported to seroconvert to rotavirus with high, virus-specific antibody titers, no studies on cell-mediated immune responses have been conducted with an NHP model in the context of rotavirus (11,14,29,36,43). One reason is that clinical disease associated with rotavirus infection in NHPs, which has been reported to be limited to the first days or weeks of life (20,21,29,36,42), is difficult to produce experimentally.In this study, the cell-mediated immunological responses to rotavirus infection in juvenile rhesus macaques that were housed in biosafety level 2 facilities of the Tulane National Primate Research Center (TNPRC) were evaluated. We anticipated that cell-mediated immune responses could be measured in these animals by the time passive maternally acquired immunity subsided, i.e., at between 4 and 6 months of age. Thus, we studied the T lymphocytes collected from peripheral blood of juvenile rhesus macaques after a detectable rotavirus infection. Based on recent studies with the adult mouse model (4, 5, 24), our hypothesis was that immunological memory in rotav...

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Section: Discussionmentioning

confidence: 99%

Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

Sestak

McNeal

Choi

et al. 2004

J Virol

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“…Currently studies are under way to test these hypotheses. Previous studies have demonstrated that trafficking mechanisms using the integrin ␣ 4 ␤ 7 have been shown to have an important role in targeting B lymphocytes to the intestine following RV infection (21,22). Alternatively, many chemokines and cytokines are implicated as chemoattractants in B cell recruitment to specific sites (23) and could be possible factors that account for the increase in the percentage of activated B cells in the PP and MLN following RV infection.…”

Section: Discussionmentioning

confidence: 99%

Early Response to Rotavirus Infection Involves Massive B Cell Activation

Blutt¹,

Warfield²,

Lewis

et al. 2002

The Journal of Immunology

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Rotavirus is an acute enteric pathogen which induces severe diarrhea in infants and children. To determine the immune response to rotavirus in vivo, we used a mouse model of rotavirus infection. We observed dramatic increases in the sizes of both Peyer’s patches and mesenteric lymph nodes, but not spleen, between 1 and 6 days after infection with a homologous strain of murine rotavirus, EC wild type. Histological analysis showed large increases in the numbers of lymphocytes in these same tissues in rotavirus-infected mice. Flow cytometric analysis confirmed the increase in numbers of lymphocytes and revealed a large increase in the percentage of activated B, but not T, lymphocytes in both Peyer’s patches and mesenteric lymph nodes of rotavirus-infected mice compared with control mice. Fragment cultures from these tissues established at 3–4 days postinfection contain rotavirus-specific IgM but not IgA Ab. A similar degree of lymphoid hyperplasia and percentage of activated B cells were observed in rotavirus-infected TCR knockout mice. Taken together, our findings show that rotavirus infection, in the context of a normal immune response, induces a large increase in the percentages of activated B cells in the absence of any detectable increase in the percentage of activated T cells, implicating a T cell-independent B cell response as the primary mechanism for initial rotavirus clearance.

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“…In support of this model, splenic murine RV-specific memory CD8 ϩ T cells that have an in vivo antiviral effect preferentially express the intestinal homing receptor, the integrin ␣4␤7 (35). Nonetheless, the expression of this receptor does not seem to be essential for the migration of the CD8 ϩ T cells to the intestine or the effectiveness of their in vivo antiviral function (25).…”

Section: ؉ T Cells That Secrete Gamma Interferon Adult Cytomegalovirmentioning

confidence: 99%

Frequencies of Virus-Specific CD4⁺and CD8⁺T Lymphocytes Secreting Gamma Interferon after Acute Natural Rotavirus Infection in Children and Adults

Jaimes

Rojas

González

et al. 2002

J Virol

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Human rotavirus-specific CD4؉ and CD8 ؉ T-cell responses in peripheral blood lymphocytes were studied using a flow cytometric assay that detects the intracellular accumulation of cytokines after short-term in vitro antigen stimulation. The frequencies of virus-specific T cells that secrete gamma interferon and interleukin-13 (IL-13) were determined in adults and children during the acute or convalescent phase of rotavirus-induced diarrhea, in asymptomatically infected adults and laboratory workers who worked with human stool samples containing rotavirus, and in healthy adults. Significantly higher frequencies of rotavirus-specific interferon gamma-secreting CD8؉ and CD4 ؉ T cells, but not IL-13-secreting T cells, were detected in symptomatically infected adults and exposed laboratory workers than in healthy adults and children with acute rotavirus diarrhea. The levels of rotavirus-specific T cells returned to levels found in healthy adults by 32 days after the onset of rotavirus diarrhea in most adult subjects. Children with rotavirus diarrhea had undetectable or very low levels of CD4 ؉ and CD8 ؉ T cells that secrete gamma interferon. Adult cytomegalovirus-seropositive individuals had frequencies of cytomegalovirus-specific T cells that secrete gamma interferon that were approximately 20 times the level of rotavirus-specific T cells. This result suggests that rotavirus is a relatively poor inducer of circulating memory T cells that secrete gamma interferon. The frequencies of gamma interferon-secreting CD4؉ and CD8 ؉ T cells and the frequencies of IL-13-secreting CD4 ؉ T cells responding to the T-cell superantigen staphylococcal enterotoxin B (SEB) were lower in children than in adults. In both adults and children, the frequencies of CD4 ؉ cells secreting gamma interferon in response to SEB were higher than the frequencies of cells secreting IL-13.Rotaviruses (RV) are the most important cause of severe dehydrating diarrhea in children worldwide, resulting in an estimated 480,000 to 640,000 deaths annually (5). The first vaccine approved for use in humans has recently been withdrawn by the manufacturer because it was associated with increased numbers of cases of intussusception (1). For these reasons, investigators are exploring alternative vaccination strategies to develop improved second-generation vaccine candidates. A detailed knowledge of the immune response against RV in humans will be useful for the design and/or evaluation of new RV vaccines.The RV-specific cell-mediated immune response is relatively well studied in the murine model: CD4 ϩ T cells are essential for the development of more than 90% of the RV-specific intestinal immunoglobulin A (IgA) (14). Moreover, the antibody response seems to be the main mechanism that mediates protection against RV reinfection (14,15,31). Murine RVspecific CD8 ϩ T cells have a direct antiviral effect, are involved in the timely resolution of primary RV infection, and can mediate partial protection against reinfection (13,15,31).Because RV replication is restricted to...

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α4β7 independent pathway for CD8+ T cell–mediated intestinal immunity to rotavirus

Cited by 57 publications

References 36 publications

Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

Early Response to Rotavirus Infection Involves Massive B Cell Activation

Frequencies of Virus-Specific CD4⁺and CD8⁺T Lymphocytes Secreting Gamma Interferon after Acute Natural Rotavirus Infection in Children and Adults

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α4β7 independent pathway for CD8+ T cell–mediated intestinal immunity to rotavirus

Cited by 57 publications

References 36 publications

Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

Defining T-Cell-Mediated Immune Responses in Rotavirus-Infected Juvenile Rhesus Macaques

Early Response to Rotavirus Infection Involves Massive B Cell Activation

Frequencies of Virus-Specific CD4+and CD8+T Lymphocytes Secreting Gamma Interferon after Acute Natural Rotavirus Infection in Children and Adults

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Frequencies of Virus-Specific CD4⁺and CD8⁺T Lymphocytes Secreting Gamma Interferon after Acute Natural Rotavirus Infection in Children and Adults