T Cells, T Cell Recognition Structures, and the Major Histocompatibility Complex

Studies were carried out to characterize the target cell for the activity of suppressor cells induced in highzone tolerance to deaggregated human gamma globulin (HGG). We applied an in vitro system for the initiation of an immune response, consisting of culturing spleen Iymphocytes on HGG-fed macrophages, in which initiator T cells are generated.These cells, when injected into the foot pads of syngeneic mice, recruit specific anti-HGG effector T Iymphocytes. We Although all three models are strictly antigen-specific, the third model suggests that even though the induction of the block by the suppressor T cells is antigen-specific, the suppressprs should paralyze the induction of an immune response to an unrelated antigen provided the latter is taken up and exposed by the same macrophages that were fed with the tolerogen.We applied a system in which the effects of suppressor cells can be tested during the first steps of induction of a primary T cell-dependent immune process, namely, on the level of macrophage-T cell interaction. We studied the capacity of spleen cells derived from tolerant animals to prevent the in vitro macrophage-mediated "education" of antigen-specific initiator T lymphocytes. We indicate that suppressor cells derived from HGG-tolerant animals exert their suppressive activity by injuring the macrophages presenting the tolerogen. MATERIALS AND METHODSMice. In all of our present experiments, 3-month-old BALB/c female mice were used. These mice were supplied by the Animal Breeding Center of the Weizmann Institute of Science.Adult thymectomy was performed at the age of 6 weeks and mice were tested 2 months later.Chemicals and Media. Dulbecco's modified Eagle's medium and Dulbecco's phosphate-buffered saline (Pi/NaCI) (pH 7.4) were supplied by the Cell Biology Department. RPMI 1640 was purchased from GIBCO. All culture media were supplemented with penicillin (100 units/ml), streptomycin (100 mg/ml), gramamycin (40 Mg/ml), sodium bicarbonate (24 mM), and 2-mercaptoethanol (50,MM). 2-Mercaptoethanol was purAbbreviations: HGG, human gamma globulin; HRS, histamine-rabbit serum albumin-Sepharose; KLH, keyhole limpet hemocyanin; Pi/NaCl, phosphate-buffered saline. 2405The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U. S. C. §1734 solely to indicate this fact.

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Immunological tolerance: High-dose antigen-induced suppressor cells from tolerant animals inactivate antigen-presenting macrophages

Segal

Tzehoval

Feldman

1979

“…The manner in which an immunogen sits in or floats on the membrane could decide whether a particular determinant or set of determinants was displayed or buried. T lymphocytes have been shown to recognize determinants in association with MHC products (23). Hence, it is not unlikely that products of MHC genes are components of the patch of membrane specializing in antigen presentation.…”

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confidence: 99%

Immune response genes have a variable influence on the selection of antigenic foreign and self determinants of insulin.

Cohen¹,

Talmon²,

Lev‐Ram³

et al. 1979

We studied the proliferative response of mouse T lymphocytes to determinants on ungulate insulins. The immunopotency of defined determinants on the molecule was found to be regulated by three factors: the immune response genes of the immunized mouse, the mode of presentation of insulin on cells or in adjuvant, and the intramolecular cooperativity between different determinants on the insulin molecule. Autosensitization against self determinants was observed under specific conditions. These findings emphasize the variable expression of immune response genes. Immune response (Ir) genes linked to the major histocompatibility complex (MHC) appear to restrict the response of T

“…The most prominent feature of immunocompetent cells is that they exert most of their biological functions through the interactions of their plasma membrane with cellular, particulate, or soluble components of their environment. Of particular interest in this context is the specific interaction of cytolytic T lymphocytes (CTLs) with target cells carrying relevant membrane-associated antigens (1)(2)(3). In the last decade, many studies have been devoted to the understanding of the mechanism of CTL-mediated target-cell lysis (4)(5)(6)(7).…”

mentioning

confidence: 99%

Cholesterol is a critical cellular component for T-lymphocyte cytotoxicity.

Heiniger¹,

Brunner²,

Cerottini³

1978

Preincubation of cytolytic T lymphocytes (CTLs) generated in secondary C57BL/6 anti-DBAJ2 mixed leukocyte cultures with an inhibitor of cellular cholesterol synthesis (25-OH-cholesterol) for 24 hr strongly depressed the cytolytic activity as determined in a 3-hr 5tCr assay. The effect of the inhibitor was reversed by the simultaneous addition of cholesterol or of mevalonic acid during the preincubation period (mevalonate is the product of the regulatory enzyme in the sterol synthesis pathway, 3-hydroxy-3-methylglutaryl-CoA reductase (NADP) [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.341). Because, under the same culture conditions, inhibition of DNA synthesis had no effect on CTL activity, the experiments suggest that the effect of 25-OH-cholesterol is related to its inhibitory effect on sterol synthesis, resulting in decreased levels of membrane-bound cholesterol, rather than to inhibition of cellular proliferation. The most prominent feature of immunocompetent cells is that they exert most of their biological functions through the interactions of their plasma membrane with cellular, particulate, or soluble components of their environment. Of particular interest in this context is the specific interaction of cytolytic T lymphocytes (CTLs) with target cells carrying relevant membrane-associated antigens (1-3). In the last decade, many studies have been devoted to the understanding of the mechanism of CTL-mediated target-cell lysis (4-7). Although the actual mechanism remains largely unknown, it has been shown that the lytic process can be divided into three steps: (i) binding of the effector cells to target cells; (ii) lethal damage to the target cells; and (iii) detachment of the effector cells from the target cells which subsequently disintegrate. It is generally accepted that the specificity of the lytic interaction is related to the existence of specific receptors on the plasma membrane of the effector cells that are complementary to antigenic determinants on the plasma membrane of the target cells.Little is known about the possible role of lipids in the plasma membrane of CTLs or target cells in the lytic mechanism. However, it was recently reported by Schlager et al. (8,9) that tumor cells under attack by complement-dependent cytotoxic antibody display a burst of lipid synthesis and release considerable amounts of triglycerides and cholesterol esters. Cholesterol represents a particularly specific component of plasma membranes of mammalian cells. It modulates their fluidity over a wide temperature range, due to its interference with the cooperative interactions of phospholipids (10-12) resulting in an "intermediary gel state" (13). It now appears that the fluidity of the plasma membrane may be critical for many, if not all, membrane functions. It influences the mobility of cell surface receptors and thus their ability to transmit transmembrane signals (14,15). Membrane fluidity is also involved in the regulation of membrane-bound enzymes (16) In this report we demonstrate that CTL...