Direct visualization of cross-reactive effector and memory allo-specific CD8 T cells generated in response to viral infections
Authors
Brehm, Michael A.Markees, Thomas G.
Daniels, Keith A.
Greiner, Dale L.
Rossini, Aldo A.
Welsh, Raymond M.
Document Type
Journal ArticlePublication Date
2003-04-12Keywords
AnimalsCD8-Positive T-Lymphocytes
Cell Line
Cells, Cultured
*Cytotoxicity Tests, Immunologic
Epitopes, T-Lymphocyte
Immune Tolerance
Immunity, Natural
Immunodominant Epitopes
*Immunologic Memory
Interferon Type II
Isoantigens
Lymphocyte Activation
Lymphocytic Choriomeningitis
Lymphocytic choriomeningitis virus
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Inbred CBA
Mice, Inbred DBA
Mice, Knockout
Pichinde virus
Receptors, Antigen, T-Cell, alpha-beta
Skin Transplantation
T-Lymphocyte Subsets
Tumor Cells, Cultured
Life Sciences
Medicine and Health Sciences
Metadata
Show full item recordAbstract
CD8 T cell cross-reactivity between heterologous viruses has been shown to provide protective immunity, induce immunopathology, influence the immunodominance of epitope-specific T cell responses, and shape the overall memory population. Virus infections also induce cross-reactive allo-specific CTL responses. In this study, we quantified the allo-specific CD8 T cells elicited by infection of C57BL/6 (B6) mice with lymphocytic choriomeningitis virus (LCMV). Cross-reactive LCMV-specific CD8 T cells were directly visualized using LCMV peptide-charged MHC tetramers to costain T cells that were stimulated to produce intracellular IFN-gamma in response to allogeneic target cells. The cross-reactivity between T cells specific for LCMV and allogeneic Ags was broad-based, in that it involved multiple LCMV-derived peptides, but there were distinctive patterns of reactivity against allogeneic cells with different haplotypes. Experiments indicated that this cross-reactivity was not due to the expression of two TCR per cell, and that the patterns of allo-reactivity changed during sequential infection with heterologous viruses. The allo-specific CD8 T cells generated by LCMV infection were maintained at relatively high frequencies in the memory pool, indicating that memory allo-specific CD8 T cell populations can arise as a consequence of viral infections. Mice previously infected with LCMV and harboring allo-specific memory T cells were refractory to the induction of tolerance to allogeneic skin grafts.Source
J Immunol. 2003 Apr 15;170(8):4077-86.
DOI
10.4049/jimmunol.170.8.4077Permanent Link to this Item
http://hdl.handle.net/20.500.14038/38238PubMed ID
12682237Related Resources
ae974a485f413a2113503eed53cd6c53
10.4049/jimmunol.170.8.4077
Scopus Count
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Independent regulation of lymphocytic choriomeningitis virus-specific T cell memory pools: relative stability of CD4 memory under conditions of CD8 memory T cell lossVarga, Steven Michael; Selin, Liisa K.; Welsh, Raymond M. (2001-02-13)Infection of mice with a series of heterologous viruses causes a reduction of memory CD8(+) T cells specific to viruses from earlier infections, but the fate of the virus-specific memory CD4(+) T cell pool following multiple virus infections has been unknown. We have previously reported that the virus-specific CD4(+) Th precursor (Thp) frequency remains stable into long-term immunity following lymphocytic choriomeningitis virus (LCMV) infection. In this study, we questioned whether heterologous virus infections or injection with soluble protein CD4 Ags would impact this stable LCMV-specific CD4(+) Thp memory pool. Limiting dilution analyses for IL-2-producing cells and intracellular cytokine staining for IFN-gamma revealed that the LCMV-specific CD4(+) Thp frequency remains relatively stable following multiple heterologous virus infections or protein Ag immunizations, even under conditions that dramatically reduce the LCMV-specific CD8(+) CTL precursor frequency. These data indicate that the CD4(+) and CD8(+) memory T cell pools are regulated independently and that the loss in CD8(+) T cell memory following heterologous virus infections is not a consequence of a parallel loss in the memory CD4(+) T cell population.
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Dynamics of memory T cell proliferation under conditions of heterologous immunity and bystander stimulationKim, Sung-Kwon; Brehm, Michael A.; Welsh, Raymond M.; Selin, Liisa K. (2002-06-22)By examining adoptively transferred CSFE-labeled lymphocytic choriomeningitis virus (LCMV)-immune donor T cells in Thy-1 congenic hosts inoculated with viruses or with the cytokine inducer poly(I:C), strikingly different responses of bona fide memory T cells were found in response to different stimuli. Poly(I:C) (cytokine) stimulation caused a limited synchronized division of memory CD8 T cells specific to each of five LCMV epitopes, with no increase and sometimes a loss in number, and no change in their epitope hierarchy. Homologous LCMV infection caused more than seven divisions of T cells specific for each epitope, with dramatic increases in number and minor changes in hierarchy. Infections with the heterologous viruses Pichinde and vaccinia (VV) caused more than seven divisions and increases in number of T cells specific to some putatively cross-reactive but not other epitopes and resulted in substantial changes in the hierarchy of the LCMV-specific T cells. Hence, there can be memory T cell division without proliferation (i.e., increase in cell number) in the absence of Ag and division with proliferation in the presence of Ag from homologous or heterologous viruses. Heterologous protective immunity between viruses is not necessarily reciprocal, given that LCMV protects against VV but VV does not protect against LCMV. VV elicited proliferation of LCMV-induced CD8 and CD4 T cells, whereas LCMV did not elicit proliferation of VV-induced T cells. Thus, depending on the pathogen and the sequence of infection, a heterologous agent may selectively stimulate the memory pool in patterns consistent with heterologous immunity.
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