Genome-wide CRISPR Screens in T Helper Cells Reveal Pervasive Crosstalk between Activation and Differentiation

Dipeptidyl peptidase IV (DP IV), an ectoenzyme in the cell membrane of T lymphocytes, is an important constituent in the process of lymphocyte activation. This conclusion is drawn from the following observations: (a) Proliferation of peripheral blood lymphocytes induced by mitogenic lectins (phytohemagglutinin, concanavalin A, pokeweed mitogen) is suppressed in the presence of DP IV inhibitors. This effect is specific and applies to an irreversible suicide inhibitor as well as to a competitive one in a dose-dependent fashion. (b) Inhibition of DNA synthesis was also induced by a polyclonal anti-DP IV immunoglobulin. (c) As a consequence of impaired T cell function the production of immunoglobulins by pokeweed mitogen-stimulated lymphocytes is also markedly reduced in the presence of DP IV inhibitors.

The role of dipeptidyl peptidase IV in human T lymphocyte activation. Inhibitors and antibodies against dipeptidyl peptidase IV suppress lymphocyte proliferation and immunoglobulin synthesis in vitro.

The immunological status of individuals occupationally exposed to low levels of inorganic lead has been examined and compared with that of non-exposed, age and sex-matched controls. At the time of testing the exposed population had a mean (+/- SD) blood lead concentration of 38.4 +/- 5.6 micrograms X 100 ml-1 (n = 39) compared with a mean value of 11.8 +/- 2.2 micrograms X 100 ml-1 (n = 21) for the control group. No differences in the serum concentrations of IgG, IgA and IgM between the populations were observed and there existed no correlation between blood lead concentration and serum immunoglobulin levels. In addition assessment was made of the capacity of peripheral blood mononuclear cells to respond to the mitogen phytohaemagglutinin (PHA), a correlate of T cell function, and to spontaneously lyse cells of the erythroleukaemic cell line K562, a measure of NK cell function. In neither case was there a difference between exposed and control populations and no correlation between reactivity and blood lead concentration. Although previous studies in rodents have indicated that exposure to inorganic lead resulting in similar blood lead concentrations may compromise immune competence our data suggest that no similar effect occurs in man.

Influence of chronic low-level exposure to lead on plasma immunoglobulin concentration and cellular immune function in man.

The Puromycin-Sensitive Aminopeptidase: Role in Neurological, Reproductive, Immunological and Proliferative Disorders.- Methionine Aminopeptidase: Emerging Role in Angiogenesis.- Placental Leucine Aminopeptidase.- Insulin-Regulated Aminopeptidase.- Leukotriene A4 hydrolase: Molecular Properties and Involvement in Inflammation.- Arginyl Aminopeptidase.- TRH-Degrading Aminopeptidase: A regulator and terminator of TRH action?- ERAP1 and MHC Class I Antigen Presentation.- CD13/Aminopeptidase N in Tumor Growth and Angiogenesis.- Alanyl-Aminopeptidases in Human T cells: Structures and functions.- Aminopeptidase Inhibitors as Anti-Hypertensive Drugs.- Aminopeptidase P and Vasoactive Peptides: From fundamental aspects to clinical interests.- Nematode aminopeptidases.

Aminopeptidases in biology and disease

The effect of ubenimex on the release of interleukin 1 (IL-1) and interleukin 2 (IL-2) from immuno-competent cells was studied. Ubenimex enhanced release of IL-1 from mouse peritoneal macrophages at 1.0 and 100 micrograms/ml in vitro and the release at 1.0 microgram/ml was larger. When ubenimex was administered to mice IL-1-releasing activity of the peritoneal macrophages was enhanced 3 and 5 days after the administration but not enhanced 1 day after the administration. Ubenimex also enhanced IL-2 release from rat spleen cells at 0.1 and 10 micrograms/ml, when concanavalin A (Con A) was added in the IL-2-releasing system. The enhancement was still observed with mouse spleen cells, when serum was further added. Moreover, thymocyte-proliferating activity was attained in the broths which rat spleen cells were incubated with ubenimex from 0.1 to 10 micrograms/ml in the absence and presence of Con A.

Enhancement of interleukin 1 and interleukin 2 releases by ubenimex.

Increased sensitivity of IL2-dependent cultured T cells and enhancement of in vitro IL2 production by human lymphocytes treated with Bestatin

Deoxyguanosine ( dGuo ) is a purine nucleoside phosphorylase (PNP) substrate which has been shown to inhibit T lymphoblast growth, PHA-induced cell proliferation and suppressor T cell activity. Low dGuo concentrations (0.5-5 microM) increase interleukin-2 (IL-2) sensitivity of IL-2-dependent cultured T cells (CTC). dGuo alone has no direct mitogenic effect on CTC. The increased IL-2 sensitivity of CTC was more marked in the presence of low IL-2 concentrations than high ones. CTC incubated with dGuo at 37 degrees C for 24 hrs absorbed more exogenous IL-2 than control non-treated CTC. CTC incubated at 4 degrees in the presence of dGuo did not absorb any more IL-2 than control CTC. FACS analysis further showed increased Tac expression on CTC due to dGuo . These findings indicate that a 37 degrees incubation of CTC with dGuo increases the number of CTC IL-2 receptors. dGuo was not found to increase IL-2 production by PHA-stimulated PBM. Therefore, low dGuo concentrations selectively augment the sensitivity of cells responding to IL-2 by increasing IL-2 receptors.

Low dose of deoxyguanosine increases IL-2 receptors of IL-2-dependent cultured T cells.

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Increased sensitivity of IL2-dependent cultured T cells and enhancement of in vitro IL2 production by human lymphocytes treated with Bestatin

Low dose of deoxyguanosine increases IL-2 receptors of IL-2-dependent cultured T cells.