Polyclonal MHC Ib-Restricted CD8+ T Cells Undergo Homeostatic Expansion in the Absence of Conventional MHC-Restricted T Cells

Jay, David C.; Reed-Loisel, Lisa M.; Jensen, Peter E.

doi:10.4049/jimmunol.180.5.2805

Cited by 6 publications

(13 citation statements)

References 79 publications

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“…However, in these animals, we observed substantially increased proliferation of the transferred memory CD8 T cells, compared with even normal WT animals (data not shown). This increase in division closely mirrored the rapid proliferation observed when cells (naive or memory) are adoptively transferred into lymphopenic environments, rather than the slow, continuous homeostatic turnover observed under normal steadystate conditions (33,55,56). Therefore, we limited our analysis to WT, CD4 2/2 , and MHC II 2/2 animals.…”

Section: Discussionmentioning

confidence: 96%

Homeostatic Turnover of Virus-Specific Memory CD8 T Cells Occurs Stochastically and Is Independent of CD4 T Cell Help

Choo

Murali‐Krishna

Anita

et al. 2010

The Journal of Immunology

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Memory CD8 T cells persist by Ag-independent homeostatic proliferation. To examine the dynamics of this cell turnover, we transferred lymphocytic choriomeningitis virus specific memory CD8 T cells into naive mice and analyzed their in vivo division kinetics longitudinally in individual recipients.Using mathematical modeling, we determined that proliferation of this stably maintained memory CD8 T cell population was homogeneous and stochastic with a small fraction of cells completing division at any given time with an intermitotic interval of 50 d. This homeostatic turnover was comparable between memory CD8 T cells of different viral epitope specificities and also the total memory phenotype (CD44high) CD8 T cells. It is well established that CD4 T cell help is critical for maintenance of CD8 T cells during chronic infections, but recent studies have suggested that CD4 T cell help is also required for maintenance of memory CD8 T cells following acute infections. Hence, we assessed the role of CD4 T cells in Ag-independent maintenance of memory CD8 T cells. Consistent with previous reports, we found that memory CD8 T cells declined when transferred into MHC class II-deficient mice. However, their numbers were maintained stably when transferred into CD4 T cell-deficient mice. Interestingly, their homeostatic proliferation, ability to make recall responses, and phenotype were independent of CD4 T cell help because none of these qualities were affected when memory CD8 T cells were transferred and maintained in either MHC class II- or CD4-deficient recipients.

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Section: Discussionmentioning

confidence: 96%

Homeostatic Turnover of Virus-Specific Memory CD8 T Cells Occurs Stochastically and Is Independent of CD4 T Cell Help

Choo

Murali‐Krishna

Anita

et al. 2010

The Journal of Immunology

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“…K b−/− D b−/− mice were backcrossed to C57BL/6 mice for 10 generations and were obtained from Taconic Farm (40). K b−/− D b−/− CIITA −/− mice and K b−/− D b−/− ®2M −/− mice were generated by crossing K b−/− D b−/− mice with either CIITA −/− mice or ®2M −/− mice (37). B6.129S6-H2-T23 tm1Cant /J mice, which are Qa-1 −/− , were a gift from Dr. Harvey Cantor (Harvard).…”

Section: Methodsmentioning

confidence: 99%

“…However, class Ib-restricted T cells expand to relatively large populations in the secondary lymphoid organs of K b−/− D b−/− CIITA −/− mice that lack conventional T cells selected by MHC class Ia or class II molecules (37). These mice provide an interesting model to study the potential role of class Ib-restricted T cells in virus infections.…”

Section: Introductionmentioning

confidence: 99%

An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

Chen

Jay

Fairbanks

et al. 2011

The Journal of Immunology

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Conventional MHC class Ia-restricted CD8+ T cells play a dominant role in the host response to virus infections but recent studies indicate that T cells with specificity for nonclassical MHC class Ib molecules may also participate in host defense. To investigate the potential role of class Ib molecules in anti-viral immune responses, Kb−/−Db−/−CIITA−/− mice lacking expression of MHC class Ia and class II molecules were infected with LCMV. These animals have a large class Ib-selected CD8+ T cell population and they were observed to mediate partial (but incomplete) virus clearance during acute LCMV infection as compared to Kb−/−Db−/−®2M−/− mice that lack expression of both MHC class Ia and class Ib molecules. Infection was associated with expansion of splenic CD8+ T cells and induction of granzyme B and IFN© effector molecules in CD8+ T cells. Partial virus clearance was dependent on CD8〈®+ cells. In vitro T cell re-stimulation assays demonstrated induction of a population of ®2M-dependent, MHC class Ib-restricted CD8+ T cells with specificity for viral antigen(s) and a yet to be defined nonclassical MHC molecule(s). MHC class Ib-restricted CD8+ T cell responses were also observed after infection of Kb−/−Db−/− mice, despite the low number of CD8+ T cells in these animals. Long term infection studies demonstrated chronic infection and gradual depletion of CD8+ T cells in Kb−/−Db−/−CIITA−/− mice, demonstrating that class Ia molecules are required for viral clearance. These findings demonstrate that class Ib-restricted CD8+ T cells have the potential to participate in the host immune response to LCMV.

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“…A previous study reported that deletion of MHCII could result in the accumulation of CD44 + CD8 + memory T cells [31]; therefore, we were interested in determining whether the lamina propria Tc17 cells found in MHCII −/− →WT mice were CD44 positive. Using flow cytometry, we found that lamina propria IL-17 + CD8 + TCR-β + , FOXP3 + CD8 + TCR-β + , and IFN-γ + CD8 + TCR-β + isolated from MHCII −/− →WT mice were all positive for CD44, indicating these cells have a memory cell surface marker phenotype (Supporting Information Fig.…”

Section: Il-17 + and Foxp3 + Cd8 + T Cells Are Upregulated In The Cecmentioning

confidence: 99%

“…Similarly to what was observed in the lamina propria, there was a robust induction of both Tc17 and FOXP3 + CD8 + T cells (Fig. 4) in the IELs isolated from MHCII −/− →WT ceca compared to WT→WT counterparts, suggesting that these atypical CD8 + cells are upregulated throughout the entire mucosa.A previous study reported that deletion of MHCII could result in the accumulation of CD44 + CD8 + memory T cells [31]; therefore, we were interested in determining whether the lamina propria Tc17 cells found in MHCII −/− →WT mice were CD44 positive. Using flow cytometry, we found that lamina propria IL-17 + CD8 + TCR-β + , FOXP3 + CD8 + TCR-β + , and IFN-γ + CD8 + TCR-β + isolated from MHCII −/− →WT mice were all positive for CD44, indicating these cells have a memory cell surface marker phenotype (Supporting Information Fig.…”

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confidence: 99%

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

et al. 2013

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The enteric pathogen Citrobacter rodentium induces a mucosal IL-17 response in CD4 + T helper (Th17) cells that is dependent on the Nod-like receptors Nod1 and Nod2. Here, we sought to determine whether this early Th17 response required antigen presentation by major histocompatibility complex class II (MHCII) for full induction. At early phases of C. rodentium infection, we observed that the intestinal mucosal Th17 response was fully blunted in irradiated mice reconstituted with MHCII-deficient (MHCII −/− →WT) hematopoietic cells. Surprisingly, we also observed a substantial increase in the relative frequency of IL-17 + CD8 + CD4 − TCR-β + cells (Tc17 cells) and FOXP3 + CD8 + CD4 − TCR-β + cells in the lamina propria and intraepithelial lymphocyte compartment of MHCII −/− →WT mice compared with that in WT→WT counterparts. Moreover, MHCII −/− →WT mice displayed increased susceptibility, increased bacterial translocation to deeper organs, and more severe colonic histopathology after infection with C. rodentium. Finally, a similar phenotype was observed in mice deficient for CIITA, a transcriptional regulator of MHCII expression. Together, these results indicate that MHCII is required to mount early mucosal Th17 responses to an enteric pathogen, and that MHCII regulates the induction of atypical CD8 + T-cell subsets, such as Tc17 cells and FOXP3 + CD8 + cells, in vivo. Keywords:Citrobacter rodentium r FOXP3 + CD8 + r IL-17 r MHC class II r Tc17Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionInterleukin (IL)-17A (herein referred to as IL-17) is a cytokine critical for host defense against pathogens at mucosal surfaces. In the gastrointestinal tract, induction of mucosal IL-17 secretion Correspondence: Dr. Stephen E. Girardin e-mail: stephen.girardin@utoronto.ca was shown to be associated with protection against Salmonella enterica serovar Typhymurium [1], Citrobacter rodentium [2], and Helicobacter species [3]. IL-17 exerts its mucosal protection at least in part through an increase of neutrophil recruitment and neutrophil-driven defense mechanisms. In addition, IL-17 acts in concert with IL-22 to enhance epithelial innate functions, such as antimicrobial peptide secretion, mucus secretion, proliferation, and renewal [4,5].IL-17 can be secreted by a number of cell populations, including CD4 + T helper (Th17) cells, γδ T cells, innate lymphoid cells (that C 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2013. 43: 2896-2906 Immunity to infection 2897 include lymphoid tissue inducer cells) and natural killer T (NKT) cells [6][7][8][9][10][11]. In humans, Th17 cells appear to represent the major cell population that produces IL-17 in the intestine under normal conditions, whereas in mice IL-17 is mainly produced by Th17 and γδ T cells. Th17 cell differentiation is mediated by the cytokines IL-6 and TGF-β, whereas IL-23 and IL-1β contribute to the full activation of these cells [6,12,13]. In addition to the c...

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Polyclonal MHC Ib-Restricted CD8+ T Cells Undergo Homeostatic Expansion in the Absence of Conventional MHC-Restricted T Cells

Cited by 6 publications

References 79 publications

Homeostatic Turnover of Virus-Specific Memory CD8 T Cells Occurs Stochastically and Is Independent of CD4 T Cell Help

Homeostatic Turnover of Virus-Specific Memory CD8 T Cells Occurs Stochastically and Is Independent of CD4 T Cell Help

An MHC Class Ib-Restricted CD8+ T Cell Response to Lymphocytic Choriomeningitis Virus

Constitutive induction of intestinal Tc17 cells in the absence of hematopoietic cell‐specific MHC class II expression

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