scholarly journals In Vivo Cytotoxic T Lymphocyte Elicitation by Mycobacterial Heat Shock Protein 70 Fusion Proteins Maps to a Discrete Domain and Is Cd4+ T Cell Independent

2000 ◽  
Vol 191 (2) ◽  
pp. 403-408 ◽  
Author(s):  
Qian Huang ◽  
Joan F.L. Richmond ◽  
Kimiko Suzue ◽  
Herman N. Eisen ◽  
Richard A. Young
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
T Lymphocytes ◽  
Heat Shock Protein ◽  
Fusion Proteins ◽  
Cytotoxic T Lymphocyte ◽  
Protein Domain ◽  
Cd4 T Cell ◽  
Fusion Partner

To gain insights into the mechanisms by which soluble heat shock protein (hsp) fusions can elicit CD8+ cytotoxic T lymphocytes (CTLs) against the fusion partner, mycobacterial (Mycobacterium tuberculosis) hsp70 was dissected to ascertain whether a particular hsp domain is necessary, and knockout mice were used to determine whether the fusion protein's immunogenicity is dependent on CD4+ T lymphocytes. We found that the ability to elicit CD8+ CTLs depends on a discrete 200–amino acid protein domain, indicating that the fusion protein's immunogenicity for CD8+ T cells does not require coupled chaperone function or peptide binding. Further, we found that ovalbumin (OVA).hsp70 fusion protein elicited anti-OVA CD8+ CTLs about equally well in CD4 knockout and wild-type C57BL/6 mice, and also when the hsp70 was of murine (self) origin. The ability of hsp70 fusion proteins to elicit CD4-independent CTL responses suggests that hsp70 fusion proteins may be useful for immunological prophylaxis and therapy against disease in CD4+ T cell–deficient individuals.

Enhanced Generation of Cytotoxic T Lymphocytes by Heat Shock Protein 70 Fusion Proteins Harboring Both CD8+T Cell and CD4+T Cell Epitopes

2010 ◽  
Vol 7 (5) ◽  
pp. 1715-1723 ◽  
Author(s):  
Seiji Takemoto ◽  
Makiya Nishikawa ◽  
Xin Guan ◽  
Yuji Ohno ◽  
Tomoya Yata ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
T Lymphocytes ◽  
Heat Shock Protein ◽  
Cytotoxic T Lymphocytes ◽  
Heat Shock Protein 70 ◽  
Fusion Proteins ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Epitopes

scholarly journals Protection against streptococcal cell wall-induced arthritis by pretreatment with the 65-kD mycobacterial heat shock protein.

1989 ◽  
Vol 170 (2) ◽  
pp. 449-466 ◽  
Author(s):  
M F van den Broek ◽  
E J Hogervorst ◽  
M C Van Bruggen ◽  
W Van Eden ◽  
R van der Zee ◽  
...  
Keyword(s):  
Cell Wall ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Delayed Type Hypersensitivity ◽  
Streptococcal Cell Wall ◽  
Amino Acid Homology ◽  
Lymphoid Cell Population ◽  
Shock Proteins

We report that streptococcal cell wall (SCW)-induced arthritis in rats, a T cell-dependent chronic, erosive polyarthritis, can be prevented by pretreatment of the rats with the mycobacterial 65-kD heat shock protein. This 65-kD protein shows extensive amino acid homology with prokaryotic and eukaryotic 65-kD heat shock proteins and is a ubiquitous bacterial common antigen. Both the clinical and histopathologic manifestations of the arthritis were prevented completely when rats were pretreated with 50 micrograms of 65-kD protein intraperitoneally at 35, 25, 15, or 5 d before administration of SCW. In such protected rats, SCW-specific T cell responses were suppressed, as compared with responses in arthritic rats. Pretreatment with 65-kD protein had no effect on the production of antibodies against SCW, on a nonspecific inflammatory reaction (zymosan-induced arthritis), or on general cellular immunity in vivo (delayed type hypersensitivity reaction to a nonrelated protein antigen). Furthermore, the protection against SCW arthritis was transferable by splenic T cells to naive recipients. Our data show that pretreatment with the 65-kD mycobacterial heat shock protein protects rats against a subsequent bacterium-induced arthritis. This protection is immunologically specific and resides in the lymphoid cell population.

scholarly journals In Vivo Suppression of Naive CD4 T Cell Responses by IL-2- and Antigen-Stimulated T Lymphocytes in the Absence of APC Competition

2008 ◽  
Vol 181 (5) ◽  
pp. 3323-3335 ◽  
Author(s):  
Hiroto Inaba ◽  
Meredith Steeves ◽  
Phuong Nguyen ◽  
Terrence L. Geiger
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
T Cell Responses ◽  
Cd4 T Cell ◽  
Cell Responses

scholarly journals Heat Shock Protein–Peptide Complexes, Reconstituted In Vitro, Elicit Peptide-specific Cytotoxic T Lymphocyte Response and Tumor Immunity

1997 ◽  
Vol 186 (8) ◽  
pp. 1315-1322 ◽  
Author(s):  
Nathalie E. Blachere ◽  
Zihai Li ◽  
Rajiv Y. Chandawarkar ◽  
Ryuichiro Suto ◽  
Navdeep S. Jaikaria ◽  
...  
Keyword(s):  
Heat Shock ◽  
Heat Shock Protein ◽  
T Lymphocyte ◽  
Synthetic Peptides ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Response ◽  
Lymphocyte Response ◽  
Peptide Complexes

Heat shock protein (HSP) preparations derived from cancer cells and virus-infected cells have been shown previously to elicit cancer-specific or virus-specific immunity. The immunogenicity of HSP preparations has been attributed to peptides associated with the HSPs. The studies reported here demonstrate that immunogenic HSP–peptide complexes can also be reconstituted in vitro. The studies show that (a) complexes of hsp70 or gp96 HSP molecules with a variety of synthetic peptides can be generated in vitro; (b) the binding of HSPs with peptides is specific in that a number of other proteins tested do not bind synthetic peptides under the conditions in which gp96 molecules do; (c) HSP–peptide complexes reconstituted in vitro are immunologically active, as tested by their ability to elicit antitumor immunity and specific CD8+ cytolytic T lymphocyte response; and (d) synthetic peptides reconstituted in vitro with gp96 are capable of being taken up and re-presented by macrophage in the same manner as gp96– peptides complexes generated in vivo. These observations demonstrate that HSPs are CD8+ T cell response–eliciting adjuvants.

scholarly journals Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Can Regulate Dendritic Cell–induced Activation and Cytotoxicity of CD8+ T Cells Independently of CD4+T Cell Help

1999 ◽  
Vol 189 (7) ◽  
pp. 1157-1162 ◽  
Author(s):  
Kathy D. McCoy ◽  
Ian F. Hermans ◽  
J. Henry Fraser ◽  
Graham Le Gros ◽  
Franca Ronchese
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cd8 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Cd4 T Cell ◽  
Cd4 T Cell Help ◽  
T Cell Help

The mechanisms that regulate the strength and duration of CD8+ cytotoxic T cell activity determine the effectiveness of an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8+ T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8+ T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti–CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8+ T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4+ T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8+ T cells, indicating its potential for tumor immunotherapy even in situations in which CD4+ T cell help is limited or absent.

scholarly journals HLA-derived peptides which inhibit T cell function bind to members of the heat-shock protein 70 family.

1996 ◽  
Vol 183 (2) ◽  
pp. 339-348 ◽  
Author(s):  
E Nossner ◽  
J E Goldberg ◽  
C Naftzger ◽  
S C Lyu ◽  
C Clayberger ◽  
...  
Keyword(s):  
T Cell ◽  
Heat Shock ◽  
T Lymphocytes ◽  
Heat Shock Protein ◽  
Cell Function ◽  
Peptide Binding ◽  
Hla Class I ◽  
Class I ◽  
Inhibitory Effects ◽  
Hla Class I Molecules

Synthetic peptides corresponding to sequences of HLA class I molecules have inhibitory effects on T cell function. The peptides investigated in this study have sequences corresponding to the relatively conserved region of the alpha 1 helix of HLA class I molecules that overlaps the "public epitope" Bw4/Bw6. These HLA-derived peptides exhibit inhibitory effects on T lymphocytes and have beneficial effects on the survival of allogenic organ transplants in mice and rats. Peptides corresponding to the Bw4a epitope appear most potent as they inhibit the differentiation of T cell precursors into mature cytotoxic T lymphocytes (CTL) and target cell lysis by established CTL lines and clones. To elucidate the mechanism through which these peptides mediate their inhibitory effect on T lymphocytes, peptide binding proteins were isolated from T cell lysates. We show that the inhibitory Bw4a peptide binds two members of the heat-shock protein (HSP) 70 family, constitutively expressed HSC70 and heat-inducible HSP70. Peptide binding to HSC/HSP70 is sequence specific and follows the rules defined by the HSC70 binding motif. Most intriguing, however, is the strict correlation of peptide binding to HSC/HSP70 and the functional effects such that only inhibitory peptides bind to HSC70 and HSP70 whereas noninhibitory peptides do not bind. This correlation suggests that small molecular weight HLA-derived peptides may modulate T cell responses by directly interacting with HSPs. In contrast to numerous reports of HSP70 expression at the surface of antigen-presenting cells and some tumor cells, we find no evidence that HSC/HSP70 are expressed at the surface of the affected T cells. Therefore, we believe that the peptides' immunodulatory effects are not mediated through a signaling event initiated by interaction of peptide with surface HSP, but favor a model similar to the action of other immunomodulatory compounds, FK506 and cyclosporin A, with a role for HSC/HSP70 similar to that for immunophilins, FKBPs and CyP40.

scholarly journals Plasma Membrane Expression of Heat Shock Protein 60 In Vivo in Response to Infection

1999 ◽  
Vol 67 (8) ◽  
pp. 4191-4200 ◽  
Author(s):  
Cindy Belles ◽  
Alicia Kuhl ◽  
Rachel Nosheny ◽  
Simon R. Carding
Keyword(s):  
Plasma Membrane ◽  
T Cell ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Cell Receptor ◽  
T Cell Response ◽  
Heat Shock Protein 60 ◽  
Membrane Expression ◽  
Hsp60 Expression

ABSTRACT Heat shock protein 60 (hsp60) is constitutively expressed in the mitochondria of eukaryotic cells. However, it has been identified in other subcellular compartments in several disease states and in transformed cells, and it is an immunogenic molecule in various infectious and autoimmune diseases. To better understand the factors that influence expression of hsp60 in normal cells in vivo, we analyzed its cellular and subcellular distribution in mice infected with the intracellular bacterium Listeria monocytogenes. Western blotting of subcellular fractionated spleen cells showed that although endogenous hsp60 was restricted to the mitochondria in noninfected animals, it was associated with the plasma membrane as a result of infection. The low levels of plasma membrane-associated hsp60 seen in the livers in noninfected animals subsequently increased during infection. Plasma membrane hsp60 expression did not correlate with bacterial growth, being most evident during or after bacterial clearance and persisting at 3 weeks postinfection. Using flow cytometry, we determined that Mac-1+, T-cell receptor γδ+, and B220+ cells represented the major Hsp60+ populations in spleens of infected mice. By contrast, B220+ cells were the predominant hsp60+ population in livers of infected mice. Of the immune cells analyzed, the kinetic profile of the γδ T-cell response most closely matched that of hsp60 expression in both the spleen and liver. Collectively, these findings show that during infection hsp60 can be localized to the plasma membrane of viable cells, particularly antigen-presenting cells, providing a means by which hsp60-reactive lymphocytes seen in various infectious disease and autoimmune disorders may be generated and maintained.

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