One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.

https://science.sciencemag.org/content/sci/271/5256/1734.full.pdf

Enhancement of antitumor immunity by CTLA-4 blockade.

Antigen-presenting cells contain a specialized late endocytic compartment, MIIC (major histocompatibility complex [MHC] class II-enriched compartment), that harbors newly synthesized MHC class II molecules in transit to the plasma membrane. MIICs have a limiting membrane enclosing characteristic internal membrane vesicles. Both the limiting membrane and the internal vesicles contain MHC class II. In this study on B lymphoblastoid cells, we demonstrate by immunoelectron microscopy that the limiting membrane of MIICs can fuse directly with the plasma membrane, resulting in release from the cells of internal MHC class II-containing vesicles. These secreted vesicles, named exosomes, were isolated from the cell culture media by differential centrifugation followed by flotation on sucrose density gradients. The overall surface protein composition of exosomes differed significantly from that of the plasma membrane. Exosome-bound MHC class II was in a compact, peptide-bound conformation. Metabolically labeled MHC class II was released into the extracellular medium with relatively slow kinetics, 10 +/- 4% in 24 h, indicating that direct fusion of MIICs with the plasma membrane is not the major pathway by which MHC class II reaches the plasma membrane. Exosomes derived from both human and murine B lymphocytes induced antigen-specific MHC class II-restricted T cell responses. These data suggest a role for exosomes in antigen presentation in vivo.

https://rupress.org/jem/article-pdf/183/3/1161/1107814/1161.pdf

B lymphocytes secrete antigen-presenting vesicles.

https://www.cell.com/cell/pdf/0092-8674(87)90568-X.pdf

T cell tolerance by clonal elimination in the thymus

Publisher Summary This chapter focuses on the important discovery that virus-specific cytotoxic T cells are dually specific for virus and for a self cell surface antigen encoded by the major histocompatibility complex (MHC). The initial work was carried out on the lymphocytic choriomeningitis virus system but it soon became evident that the same phenomenon applied to many other viruses. In addition, the same principle has been found to hold for other antigenic systems, such as trinitrophenyl coupled to cells, minor histocompatibility antigens, and the H-Y model. Graft rejection and the need for genetically homogeneous inbred mouse strains for cancer research led to the development of transplantation immunology and immunogenetics. The result is that the gene complex coding for major transplantation antigens is one of the better understood mammalian genetic regions. Cytotoxic T-cell specificity is comparable to serological specificity. Because quantification of specificity or cross-reactivity is difficult, and because of the technical limitations of these cytotoxic T-cell assays, results are interpreted with great reservation. MHC restriction reflects the fact that the effector function of T cells is determined by the kind of Self-H recognized together with the foreign antigen on cell surfaces: K and D are receptors for lytic signals, I determinants are receptors for cell differentiation signals that are delivered antigen-specifically by T cells.

MHC-restricted cytotoxic T cells: studies on the biological role of polymorphic major transplantation antigens determining T-cell restriction-specificity, function, and responsiveness.

The study of human hematopoietic cells and the human immune system is hampered by the lack of a suitable experimental model. Experimental data are presented showing that human fetal liver hematopoietic cells, human fetal thymus, and human fetal lymph node support the differentiation of mature human T cells and B cells after engraftment into mice with genetically determined severe combined immunodeficiency. The resultant SCID-hu mice are found to have a transient wave of human CD4+ and CD8+ T cells and human IgG (immunoglobulin G) in the peripheral circulation. The functional status of the human immune system within this mouse model is not yet known.

https://science.sciencemag.org/content/sci/241/4873/1632.full.pdf

The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function.

Basic veterinary immunology , Basic veterinary immunology , مرکز فناوری اطلاعات و اطلاع رسانی کشاورزی

/pdf/basic-veterinary-immunology-52egzepdin.pdf

Basic Veterinary Immunology

Faith, Madness, and Spontaneous Human Combustion: What Immunology Can Teach Us about Self-Perception

Murine 6C3HED lymphoma cells were found to rosette with sheep red blood cells (SRBC). Normal C3H lymphocytes did not exhibit this property. This rosetting capacity of 6C3HED cells was found to be an accurate and reproducible means for discriminating between normal and tumor cells. The SRBC receptor on these lymphoma cells appeared to be serologically distinct from that expressed by normal human T lymphocytes since reciprocal blocking experiments demonstrated that inhibitory antisera were not cross-reactive. The expression of the SRBC receptor by the 6C3HED cells appeared to correlate with the expression of a tumor-associated antigen and was spatially related to an antigen expressed by 6C3HED and normal neonatal but not adult mouse cells.

Expression of a sheep red blood cell receptor by a murine lymphoma.

The possibility was examined that K or D regulated responsiveness of virus specific cytotoxic T cells was due to the virus-specific and differential effects on expression and/or accessibility of H-2K or D products on virus-infected target cells. Cells from established lines of fibroblasts kept in tissue culture, uninfected, infected with either vaccinia virus, with lymphocytic choriomeningitis virus (LCMV) or with both LCMV plus vaccinia virus, were compared with respect to expression of Kk, Dk and Db. H-2K or D expression was assessed by: 1) absorption of defined anti-K or anti-D antisera: 2) susceptibility to alloreactive cytotoxic T cells; and 3) susceptibility to K or D restricted virus-specific cytotoxic T cells. In all 3 tests, no virus-specific effect on Kk, Dk or Db expression on all target cells (uninfected, LCMV, or vaccinia virus infected, or doubly infected) was noticed. Most importantly, H-2k target cells infected with both LCMV plus vaccinia virus, that were not lysed by low-responder Dk-restricted vaccinia specific T cells were lysed by high-responder Dk restricted LCMV-immune T cells; in contrast, these targets were lysed by Kk-restricted vaccinia specific T cells but only poorly by Kk-restricted LCMV-immune T cells. Thus, expression or accessibility of Dk could not have limited responsiveness to vaccinia virus on this target cell since Dk was accessible to Dk-restricted LCMV-specific T cells; a similar argument can be made for the accessibility of Kk. These experiments suggest that expression and/or accessibility of Kk, Dk or Db on target cells does not explain the virus- and K or D dependent responsiveness differences of virus-specific effector T cells.

G. N. Callahan

Papers

Basic Veterinary Immunology

Faith, Madness, and Spontaneous Human Combustion: What Immunology Can Teach Us about Self-Perception

Expression of a sheep red blood cell receptor by a murine lymphoma.

Low responsiveness to Dk or Db plus vaccinia virus or to Kk plus lymphocytic choriomeningitis virus assessed by availability of D or K products

Cross-reacting xenoantibodies to human and murine beta 2-microglobulin.