scholarly journals T cells specific for hapten-modified self are precommitted for self major histocompatibility complex antigens before encounter with the hapten.

1978 ◽  
Vol 147 (4) ◽  
pp. 1065-1077 ◽  
Author(s):  
C A Janeway ◽  
P D Murphy ◽  
J Kemp ◽  
H Wigzell
Keyword(s):  
T Cells ◽  
Suppressor Cells ◽  
The Other ◽  
Target Cells ◽  
Killer Cells ◽  
Effector Cells ◽  
Complex Cells ◽  
Histocompatibility Complex ◽  
Peripheral T Cells ◽  
Cytotoxic Effector

The technique of antigen-driven, 5-bromo-deoxyuridine and light suicide has been adapted to eliminate the precursors of cytotoxic effector cells both for alloantigen and for 2,4,6-trinitrophenyl(TNP)-modified stimulator and target cells. Using this technique, the following observations have been made. Precursors of killer cells specific for alloantigen can be suicided independently of precursors of killer cells specific for TNP-modified self cells. The loss of activity during this procedure is not due to either specific or nonspecific suppressor cells, as judged by mixing experiments. With responder cells from F1 animals, it has been possible to show that precursors specific for TNP-modified cells from one parent are suicided independently of precursors specific for TNP-modified cells of the other parent, but only if the parental strains differ in the K and D regions of the H-2 complex. Cells of F1 mice derived from K and D identical, I region different, parental strains were specifically suicided by TNP-modified stimulator cells from either parent. However, the cross-reactive killing of TNP-self targets induced by stimulation with allogeneic cells is not eliminated by first suiciding with TNP-parental cells, suggesting that the precursors of these two types of TNP-self killer cells are different. This is compatible with reported differences in their specificity, as confirmed in this report. Finally, deletion of alloreactive cells by this technique reveals little or no reactivity specific for TNP-modified allogeneic stimulator cells. In summary, these results strongly suggest that recognition of self MHC antigens is preprogrammed in peripheral T cells of normal animals, and is not acquired during the immunization process. They also suggest that cells specific for modified alloantigen are relatively rare in the strains of mice studied.

scholarly journals Regulation of T Cells in Cancer by Nitric Oxide

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2655
Author(s):  
Inesa Navasardyan ◽  
Benjamin Bonavida
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Suppressor Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Target Cells ◽  
Effector Cells ◽  
Cell Functions

The T cell-mediated immune response is primarily involved in the fight against infectious diseases and cancer and its underlying mechanisms are complex. The anti-tumor T cell response is regulated by various T cell subsets and other cells and tissues in the tumor microenvironment (TME). Various mechanisms are involved in the regulation of these various effector cells. One mechanism is the iNOS/.NO that has been reported to be intimately involved in the regulation and differentiation of the various cells that regulate the anti-tumor CD8 T cells. Both endogenous and exogenous .NO are implicated in this regulation. Importantly, the exposure of T cells to .NO had different effects on the immune response, depending on the .NO concentration and time of exposure. For instance, iNOS in T cells regulates activation-induced cell death and inhibits Treg induction. Effector CD8 T cells exposed to .NO result in the upregulation of death receptors and enhance their anti-tumor cytotoxic activity. .NO-Tregs suppress CD4 Th17 cells and their differentiation. Myeloid-derived suppressor cells (MDSCs) expressing iNOS inhibit T cell functions via .NO and inhibit anti-tumor CD8 T cells. Therefore, both .NO donors and .NO inhibitors are potential therapeutics tailored to specific target cells that regulate the T cell effector anti-tumor response.

scholarly journals The major histocompatibility complex determines susceptibility to cytotoxic T cells directed against minor histocompatibility antigens.

1975 ◽  
Vol 142 (6) ◽  
pp. 1349-1364 ◽  
Author(s):  
M J Bevan
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cytotoxic T Cells ◽  
Target Cells ◽  
Major Histocompatibility ◽  
Effector Cells ◽  
Minor Histocompatibility Antigens ◽  
Cytotoxic Cells ◽  
Histocompatibility Complex ◽  
Self Recognition

Cytotoxic cells were generated by immunizing one strain of mouse with cells from an allogeneic strain which carries the same H-2 region. The effector cells assayed in a 4 h 51Cr release assay were shown to be T cells and indistinguishable, except in specificity, from cytotoxic T cells directed at H-2 alloantigens. Although the genetic differences between responder and stimulator cells responsible for the immunization did not code in H-2, the H-2 complex did restrict susceptibility of target cells. For example, BALB.B cytotoxic cells (H-2b) immunized against and capable of lysing C57BL/6 cells (H-2b) would not lyse B6.C/H-2d target cells. C57BL/6 and B6.C/H-2d are congenic and differ in the H-2 region. Two hypotheses are considered to explain the H-2 restriction of susceptibility to cytotoxic T cells generated by an H-2 identical alloimmunization. (a) The dual (self) recognition hypothesis states that the cytotoxic cell has two recognition units, one for H-2-coded structures and another clonally restricted receptor for the minor alloantigen. (b) The interaction antigen hypothesis states that all the surface alloantigenic determinants recognized by cytotoxic T cells are the result of interaction between H-2- and non-H-2-coded gene products. Two lines of evidence, one with F1 effector cells and the other a cold target competition experiment, are presented which argue strongly in favor of the interaction antigen hypothesis. The regions of H-2 required to be histocompatible were mapped to the D region and to the left of IC, probably the K region. These results, and recent work on the response to virus-infected and TNP-modified syngeneic cells, suggest that cytotoxic cells are restricted in specificity to preferentially recognizing alterations in structures that are coded in the major histocompatibility complex.

scholarly journals Regulation of in vitro cytotoxic T lymphocyte generation. I. Evidence that killer cell precursors differentiate to effector cells in two steps.

1982 ◽  
Vol 155 (3) ◽  
pp. 783-796 ◽  
Author(s):  
A Schwartz ◽  
S L Sutton ◽  
R K Gershon
Keyword(s):  
T Cells ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Killer Cell ◽  
Suppressor Cells ◽  
Target Cells ◽  
Suppressor T Cells ◽  
Effector Cells ◽  
Step Process

The differentiation of cytotoxic T lymphocyte precursor cells (CTL-P) into CTL effector cells is a two-step process. In the first step, naïve CTL-P (CTL-PN) become activated (CTL-PA) but do not yet have the capacity to kill target cells. CTL-PA can be distinguished from CTL-PN because the former are far less sensitive than the latter to the effects of in vitro-generated suppressor cells. Thus, the addition of suppressor T cells (Ts) to a fresh MLC can totally inhibit the production of CTL from CTL-PN, whereas the same Ts only minimally affect the generation of CTL from CTL-PA. It is not known whether these Ts act directly on CTL-PN or on a helper cell needed for activation to CTL-PA. The production of CTL-PA can take place in allogeneic mixed leukocyte cultures (MLC) treated with the drug pyrilamine, or when heat-inactivated stimulator cells are used. Each of these treatments inhibits the differentiation of CTL-PA to CTL. However, if pyrilamine is removed, a nonspecific MLC-derived signal can induce these CTL-PA to become CTL, even in the presence of significant numbers of Ts. This two step process of differentiation of CTL-P to CTL may be analogous to the way naïve B cells become antibody-producing cells.

scholarly journals Allosuppressor and allohelper T cells in acute and chronic graft-vs-host disease. I. Alloreactive suppressor cells rather than killer T cells appear to be the decisive effector cells in lethal graft-vs.-host disease.

1982 ◽  
Vol 155 (5) ◽  
pp. 1501-1522 ◽  
Author(s):  
A G Rolink ◽  
T Radaszkiewicz ◽  
S T Pals ◽  
W G van der Meer ◽  
E Gleichmann
Keyword(s):  
T Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Suppressor Cells ◽  
Activated T Cells ◽  
Killer Cells ◽  
Host Disease ◽  
Effector Cells ◽  
Graft Vs Host Disease ◽  
T Killer Cells

Splenic T cells from B10 donors were injected into irradiated (B10 x DBA/2)F1 mice. Either 5 or 6 d later, activated donor T cells were recovered from the spleens of these primary F1 (1 degree F1) recipients and transferred to groups of nonirradiated syngeneic F1 (2 degrees F1) recipients. Whereas day-5-activated parental T cells induced the characteristic symptoms of acute graft-vs.-host disease (GVHD) and eventually lethal GVHD, day-6-activated B10 T cells failed to induce acute GVHD but induced symptoms of chronic GVHD. Interestingly, the inability of day-6-activated T cells to induce lethal GVHD could not be ascribed to a lack in anti-F1 T killer cells. The combined results of functional studies indicated that day-6 cells were enriched for alloreactive helper T cells, whereas day-5 cells were enriched for alloreactive suppressor cells. Hence, our findings indicate that acute GVHD and lethal GVHD are caused by alloreactive donor T suppressor but not T killer cells, and that symptoms of chronic GVHD are caused by alloreactive donor T helper cells.

scholarly journals Expression of HLA-C molecules confers target cell resistance to some non-major histocompatibility complex-restricted T cells in a manner analogous to allospecific natural killer cells.

1995 ◽  
Vol 182 (4) ◽  
pp. 1005-1018 ◽  
Author(s):  
C S Falk ◽  
A Steinle ◽  
D J Schendel
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Nk Cells ◽  
Natural Killer ◽  
Target Cell ◽  
Target Cells ◽  
Cell Resistance ◽  
Effector Cells ◽  
Histocompatibility Complex

Specific HLA molecules have recently been shown to confer target cell resistance to lysis by some CD3- natural killer (NK) cells. For certain NK clones, resistance is governed by two specificities (NK1 and NK2) that are associated with particular HLA-C alleles: in general, target cells expressing Cw1, Cw3, Cw7, or Cw8 are susceptible to NK1 but resistant to NK2 clones, whereas target cells expressing Cw2, Cw4, Cw5, or Cw6 are susceptible to NK2 and resistant to NK1 cells. These two clusters of HLA-C alleles are distinguished by a dimorphism in the alpha 1 helical region, localized at amino acid positions 77 and 80. In this report, we show that highly enriched CD3+/CD56- cytotoxic T cell sublines and CD3-/CD56+ NK sublines derived from the same donor have identical cytolytic specificities when tested against a panel of allogeneic LCL and various HLA-B and -C transfectant cell lines. The lysis pattern of the allogeneic cells appeared to be related to the NK2 specificity for both effector cells: LCL expressing HLA-Cw2, Cw4, Cw5, or Cw6 alleles were lysed, while LCL expressing HLA-Cw1, Cw3, or Cw7 molecules were resistant. Resistance to lysis could be conferred to susceptible target cells by transfection with a Cw*0702 gene, while expression of a Cw*0602 gene did not provide protection. Similar patterns of HLA-C-mediated resistance were also found with two polyclonal T cell lines generated from the peripheral blood lymphocytes of unrelated donors. Thus, major histocompatibility complex (MHC) molecules that induced resistance to particular NK cells also regulated target cell resistance to lysis by these non-MHC-restricted effector T cells. For both types of effector cells, direct binding to HLA-C molecules was necessary to achieve inhibition since preincubation with mAb specific for class I molecules destroyed the protection from lysis of HLA-Cw7 expressing target cells. mAbs specific for CD3 and CD8 molecules had no influence on lysis or inhibition of the NK-like T cells. Formation of MHC complexes with particular peptides did not appear to be essential to confer resistance, since a cell line with defective peptide transporter genes (TAP genes), when transfected with an appropriate HLA-C allele, was as resistant to lysis as HLA-C transfectant lines with normal TAP function. These results suggest that HLA-C molecules may deliver negative regulatory signals to some non-MHC-restricted T cells in a manner similar to that described previously for particular NK cells.

scholarly journals Hyaluronan binding function of CD44 is transiently activated on T cells during an in vivo immune response.

1994 ◽  
Vol 180 (1) ◽  
pp. 383-387 ◽  
Author(s):  
J Lesley ◽  
N Howes ◽  
A Perschl ◽  
R Hyman
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Surface Receptor ◽  
Target Cells ◽  
Cd44 Isoforms ◽  
Effector Cells ◽  
Binding Function ◽  
Cytotoxic Effector

Though CD44 functions as a cell surface receptor for hyaluronan (HA) in some cell lines, most normal hematopoietic cells expressing CD44 do not bind HA. Certain CD44-specific monoclonal antibodies (mAbs) can rapidly induce CD44-mediated HA binding in normal murine T cells. This observation suggests that in vivo mechanisms may exist for activating the HA receptor function of CD44 on normal T cells. Here, it is shown that up to one third of splenic T cells are capable of CD44-mediated binding of fluorescein-conjugated HA (Fl-HA) during an in vivo allogeneic response. HA binding activity peaks at 7-8 d postinjection and declines rapidly. These rapid kinetics could be the result of transient activation of CD44 function and/or differentiation or expansion of short-lived population(s) that have constitutive HA-binding function. Both CD4 and CD8 T cells are included in the HA binding population which is strongly CD44 positive. After separation of HA-binding cells from nonbinding cells by cell sorting, it is shown that almost all cytotoxic effector cells are found in the HA-binding population. However, there is no evidence that CD44-mediated HA recognition is directly involved in the killing of target cells, since cytotoxicity could not be inhibited by CD44-specific mAbs that inhibit HA binding or by soluble HA. PCR amplification of cDNA reverse transcribed from RNA of sorted HA-binding cells indicated no evidence for CD44 isoforms other than the standard (hematopoietic) form. Though CD44 expression is known to be elevated upon T cell activation, and, as shown here, HA-binding function is induced in a portion of CD44-expressing T cells including cytotoxic effector cells, the role of CD44 and HA-recognition in immune responses is not known.

Role of NKG2D signaling in the cytotoxicity of activated and expanded CD8+ T cells

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 3065-3072 ◽  
Author(s):  
Michael R. Verneris ◽  
Mobin Karami ◽  
Jeanette Baker ◽  
Anishka Jayaswal ◽  
Robert S. Negrin
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Interleukin 2 ◽  
Cell Receptor ◽  
Malignant Cell ◽  
Leukemic Cells ◽  
Target Cells ◽  
High Dose ◽  
Effector Cells ◽  
Nkg2d Expression

Abstract Activating and expanding T cells using T-cell receptor (TCR) cross-linking antibodies and interleukin 2 (IL-2) results in potent cytotoxic effector cells capable of recognizing a broad range of malignant cell targets, including autologous leukemic cells. The mechanism of target cell recognition has previously been unknown. Recent studies show that ligation of NKG2D on natural killer (NK) cells directly induces cytotoxicity, whereas on T cells it costimulates TCR signaling. Here we demonstrate that NKG2D expression is up-regulated upon activation and expansion of human CD8+ T cells. Antibody blocking, redirected cytolysis, and small interfering RNA (siRNA) studies using purified CD8+ T cells demonstrate that cytotoxicity against malignant target cells occurs through NKG2D-mediated recognition and signaling and not through the TCR. Activated and expanded CD8+ T cells develop cytotoxicity after 10 to 14 days of culture, coincident with the expression of the adapter protein DAP10. T cells activated and expanded in low (30 U/mL) and high (300 U/mL) concentrations of IL-2 both up-regulated NKG2D expression equally, but only cells cultured in high-dose IL-2 expressed DAP10 and were cytotoxic. Collectively these results establish that NKG2D triggering accounts for the majority of major histocompatibility complex (MHC)–unrestricted cytotoxicity of activated and expanded CD8+ T cells, likely through DAP10-mediated signaling. (Blood. 2004;103: 3065-3072)

scholarly journals Cell-mediated lympholysis to H-2-matched target cells modified with a series of nitrophenyl compounds.

1976 ◽  
Vol 144 (4) ◽  
pp. 1134-1140 ◽  
Author(s):  
T G Rehn ◽  
J K Inman ◽  
G M Shearer
Keyword(s):  
T Cell ◽  
Target Cells ◽  
Cell Recognition ◽  
Receptor Model ◽  
Spleen Cells ◽  
Effector Cells ◽  
T Cell Recognition ◽  
Cytotoxic Effector

The specificity of C57BL/10 cytotoxic effector cells generated by in vitro sensitization with autologous spleen cells modified with a series of related nitrophenyl compounds was investigated. The failure of trinitrophenyl (TNP)-sensitized effector cells to lyse TNP-beta-alanylglycylglycyl(AGG)-modified target cells is presented as evidence contradicting the intimacy or dual receptor model or T-cell recognition in its simplest form. Data are also shown indicating that sensitization with N-(3-nitro-4-hydroxy-5-iodophenylacetyl)-AGG-modified stimulating cells generates noncross-reacting clones of cytotoxic effector cells.

scholarly journals IL-36γ-armed oncolytic virus exerts superior efficacy through induction of potent adaptive antitumor immunity

2021 ◽  
Author(s):  
Min Yang ◽  
Esther Giehl ◽  
Chao Feng ◽  
Mathilde Feist ◽  
Hongqi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
Therapeutic Efficacy ◽  
Oncolytic Virus ◽  
Antitumor Immunity ◽  
Human Cancer ◽  
Suppressor Cells ◽  
T Cell Differentiation ◽  
Effector Cells ◽  
Superior Efficacy ◽  
Vaccinia Viruses

AbstractIn this study, we aimed to apply the cytokine IL-36γ to cancer immunotherapy by constructing new oncolytic vaccinia viruses (OV) expressing interleukin-36γ (IL-36γ-OVs), leveraging unique synergism between OV and IL-36γ’s ability to promote antitumor adaptive immunity and modulate tumor microenvironment (TME). IL-36γ-OV had dramatic therapeutic efficacies in multiple murine tumor models, frequently leading to complete cancer eradication in large fractions of mice. Mechanistically, IL-36-γ-armed OV induced infiltration of lymphocytes and dendritic cells, decreased myeloid-derived suppressor cells and M2-like tumor-associated macrophages, and T cell differentiation into effector cells. Further study showed that IL-36γ-OV increased the number of tumor antigen-specific CD4+ and CD8+ T cells and the therapeutic efficacy depended on both CD8+ and CD4+ T cells. These results demonstrate that these IL36γ-armed OVs exert potent therapeutic efficacy mainly though antitumor immunity and they may hold great potential to advance treatment in human cancer patients.

scholarly journals T cell regulation of b cell activation. Cloned Lyt-1+2-T suppressor cells inhibit the major histocompatibility complex-restricted interaction of T helper cells with B cells and/or accessory cells.

1983 ◽  
Vol 158 (4) ◽  
pp. 1178-1190 ◽  
Author(s):  
Y Asano ◽  
R J Hodes
Keyword(s):  
Major Histocompatibility Complex ◽  
B Cells ◽  
Cell Activation ◽  
Suppressor Cells ◽  
Major Histocompatibility ◽  
T Helper ◽  
Th Cells ◽  
Effector Cells ◽  
Histocompatibility Complex ◽  
Accessory Cells

The present studies have identified cloned Lyt-1+2- T suppressor (Ts) cells that are both antigen specific and major histocompatibility complex (MHC) restricted in their activation requirements and that function to regulate the MHC-restricted activation of B cells by T helper (Th) cells. ParentA-restricted Ts clones suppressed, in antigen-specific fashion, the responses generated by (A X B)F1 Th cells cooperating with parentA (B plus accessory) cells, but did not suppress responses by the same (A X B)F1 Th cell population cooperating with parentB (B plus accessory) cells. Moreover, responses of (A X B)F1 leads to parentA Th cells and (A X B)F1 (B plus accessory) cells were suppressed by parentA-restricted Ts clones but not by parentB-restricted Ts clones. Thus, these findings suggest that the cloned Ts cells that have been characterized here function by specifically inhibiting the MHC-restricted interaction between Th cells and B and/or accessory cells. It was further demonstrated in experiments using cloned Th and Ts populations that these Lyt-1+2-Ts cells act not simply as inducers of suppressor but rather function in a restricted fashion as effector cells in the suppressor pathway.

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