ABSTRACT
Herpetic stromal keratitis (HSK) is an inflammatory disorder induced by HSV-1 infection and characterized by T cell-dependent destruction of corneal tissues. It is not known what triggers CD4(+) T cell migration into the stroma of HSV-1-infected corneas. The keratocyte is a fibroblast-like cell that can function as an antigen-presenting cell in the mouse cornea by expressing MHC class II and costimulatory molecules after HSV-1 infection. We hypothesized that chemokines produced by stromal keratocytes are involved in CD4(+) T cell infiltration into the cornea. We found that keratocytes produce several cytokines and chemokines, including MCP-1, RANTES, and T cell activation (TCA)-3. HSV-1 infection increased the production of MCP-1 and RANTES by keratocytes, and these acted as chemoattractants for HSV-1-primed CD4(+) T cells expressing CCR2 and CCR5. Expression of MCP-1 in the corneal stroma was confirmed in vivo. Finally, when HSV-1-primed CD4(+) T cells were adoptively transferred into wild type and MCP-1-deficient mice that had been sublethally irradiated to minimize chemokine production from immune cells, infiltration of CD4(+) T cells was markedly reduced in the MCP-1-deficient mice, suggesting that it is the MCP-1 from HSV-1-infected keratocytes that attracts CD4(+) T cells into the cornea.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Chemokine CCL2/physiology , Corneal Stroma/immunology , Keratitis, Herpetic/immunology , Adoptive Transfer , Animals , CD8-Positive T-Lymphocytes/immunology , Cell Movement , Cells, Cultured , Chemokine CCL1/genetics , Chemokine CCL1/metabolism , Chemokine CCL5/genetics , Chemokine CCL5/metabolism , Chemokines/genetics , Chemokines/metabolism , Corneal Stroma/virology , Cytokines/genetics , Cytokines/metabolism , Enzyme-Linked Immunosorbent Assay , Epithelium, Corneal/cytology , Epithelium, Corneal/metabolism , Fibroblasts/immunology , Fibroblasts/virology , Flow Cytometry , Herpesvirus 1, Human/physiology , Humans , Immunoenzyme Techniques , Mice , Mice, Inbred BALB C , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptors, Chemokine/genetics , Receptors, Chemokine/metabolism , Reverse Transcriptase Polymerase Chain ReactionABSTRACT
Techniques for modulating immune cells for cancer therapy have been widely studied. One key approach that is being clinically tested is developing tumor-destructive cell-mediated immune responses by regulating co-stimulatory molecules. 4-1BB (CD137), a member of the TNF receptor family, is expressed following activation of T and NK cells. Recently, it has been reported that DCs also express 4-1BB. Cross-linking of 4-1BB provides a potent co-stimulatory signal for lymphocytes via signal transduction pathways that modulate a number of cellular responses. One remarkable response is stimulation of anti-tumor activity in vivo and in vitro. We here review the potential role of 4-1BB in cancer immunotherapy focusing on the cellular and molecular mechanisms involved.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents/pharmacology , Neoplasms/therapy , Receptors, Nerve Growth Factor/antagonists & inhibitors , Receptors, Tumor Necrosis Factor/antagonists & inhibitors , Animals , Antigens, CD/drug effects , Antigens, CD/immunology , Antineoplastic Agents/therapeutic use , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/metabolism , Humans , Immunotherapy , Lymphocyte Activation , Neoplasms/immunology , Receptors, Nerve Growth Factor/drug effects , Receptors, Nerve Growth Factor/immunology , Receptors, Tumor Necrosis Factor/drug effects , Receptors, Tumor Necrosis Factor/immunology , Signal Transduction/immunology , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Tumor Necrosis Factor Receptor Superfamily, Member 9ABSTRACT
Heat shock protein 72 (Hsp72) is thought to protect cells against cellular stress. The protective role of Hsp72 was investigated by determining the effect of this protein on the stress-activated protein kinase signaling pathways. Prior exposure of NIH 3T3 cells to mild heat shock (43 degrees C for 20 min) resulted in inhibition of H(2)O(2)-induced activation of apoptosis signal-regulating kinase 1 (ASK1). Overexpression of Hsp72 also inhibited H(2)O(2)-induced activation of ASK1 as well as that of downstream kinases in the p38 mitogen-activated protein kinase (MAPK) signaling cascade. Recombinant Hsp72 bound directly to ASK1 and inhibited ASK1 activity in vitro. Furthermore, coimmunoprecipitation analysis revealed a physical interaction between endogenous Hsp72 and ASK1 in NIH 3T3 cells exposed to mild heat shock. Hsp72 blocked both the homo-oligomerization of ASK1 and ASK1-dependent apoptosis. Hsp72 antisense oligonucleotides prevented the inhibitory effects of mild heat shock on H(2)O(2)-induced ASK1 activation and apoptosis. These observations suggest that Hsp72 functions as an endogenous inhibitor of ASK1.