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.

We use antibacterial soap to wash our hands, we swab doorknobs with antibacterial wipes, we pop antibiotics at the first sign of disease - all to avoid infection But we are all infected From before birth to after death, infection is what makes humans human In a startling, chilling, and inspiring narrative, veteran microbiologist, and author Gerald Callahan, explores the world of the microscopic creatures that live on, in, and around us Did you know that: our overuse of antibiotics is placing us on then cusp of a resurgence of diseases we had thought long conquered? and, many ailments - from schizophrenia and gastric ulcers to obsessive-compulsive disorder - are now being linked to infections? Infection will awaken you to the microscopic brethren that ensure our health as well as take it from us For better or worse, infection shapes our lives

Infection: The Uninvited Universe

H-2 and ia antigens in mouse serum. Abstr.

Antigens associated with the H-2Kk and I-Ak regions of the major histocompatibility complex have been identified with monoclonal antibodies on an in vivo grown murine alveologenic adenocarcinoma, LT-85. Immunoprecipitation and sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis demonstrated differences in the molecular structure of I-Ak region-coded antigens between LT-85 and host C3H/HeN mammary tumor virus-negative (MTV-) or autologous C3HfB/HeN splenocytes. Ia antigens derived from LT-85 tumor cells exhibited both an increased heterogeneity in the alpha-chain and a lower apparent molecular weight in the beta-chain. Tryptic peptide mapping of the I-Ak antigen alpha- and beta-chains derived from C3H/HeN MTV- mice and LT-85 tumor cells revealed a single peptide difference in the beta-chains of these antigens. Results obtained with neuraminidase-treated I-Ak beta-chains indicated that this difference was not due to sialic and content. Maintenance of LT-85 in vitro, even for short periods, resulted in the loss of these I-Ak antigens. However, this loss of I-Ak antigen expression was fully reversible with in vivo growth.

Identification of la Antigens on the Murine Adenocarcinoma L T-85

A cell surface antigen was isolated from soluble extracts of rat lymphoid cells. Molecular weight of the purified antigen was estimated by SDS gel electrophoresis to be 10 to 20,000 daltons. Physical as well as immunologic properties of this antigen do not resemble those of any known antigenic product of the major histocompatibility locus of the rat. It is therefore proposed that it is a rat minor histocompatibility antigen.

Rat Cell Surface Antigens II. Isolation of a Minor Histocompatibility Antigen

A/JCr mice reject SalN fibrosarcoma cells genetically engineered to express major histocompatibility complex (MHC) class II molecules and are highly resistant to subsequent challenge with unmodified S

G. N. Callahan

Papers

Infection: The Uninvited Universe

H-2 and ia antigens in mouse serum. Abstr.

Identification of la Antigens on the Murine Adenocarcinoma L T-85

Rat Cell Surface Antigens II. Isolation of a Minor Histocompatibility Antigen

Protective antitumor immunity induced by immunization with MHC class II gene-transfected tumor cells is unrelated to MHC class II expression.