Antigen‐specific suppression of cytotoxic T cell responses in mice. I. Suppressor T cells are not cytotoxic cells
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Abstract The main conclusion from these experiments is that the antigen‐specific suppressor T cell of mice which inhibits the induction of cytotoxic T lymphocytes is not itself a cytotoxic T cell. This conclusion is supported by two main observations: first, a certain cell number from first‐step cultures which was suppressive in the presence of a high dose of antigen actually helped the cytotoxic response at a lower antigen dose. This observation is difficult to reconcile with the hypothesis that suppression is due to the killing of the stimulator or the responder cells in the second‐step culture by cytotoxic T cells. Second, cells from first‐step cultures of cortisone‐treated mice displayed cytotoxic activity but had no suppressive effect on the generation of killer cells. It was further demonstrated that these cells failed to influence in any way the suppressive effect, however weak, of cells from first‐step cultures of normal spleen. We therefore favor the view that the suppression observed in this system is due to a regulatory signal which occurs as a result of the ability of both inhibitory cells and responder cells to recognize and respond to allogeneic determinants expressed on the surface of stimulator cells. The suppressor T cells described here act by linked associative recognition of antigen. That is, suppressor T cells only inhibit the induction of a precursor cytotoxic T cell in the presence of an antigen to which both the precursor cell and the suppressor cell can bind. In this sense, suppressors act in a manner analogous to helper T cells in T‐B cell cooperation; carrier‐specific helper T cells only enhance an anti‐hapten B cell response in the presence of hapten‐carrier conjugates. Similarly, alloantigen a (carrier)‐specific suppressor T cells only inhibit alloantigen b (hapten)‐specific cytotoxic responses in the presence of (a × b)F 1 stimulator cells (hapten‐carrier conjugate), not in the presence of a mixture of parental stimulator cells (a + b).Monocyte
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ABSTRACT Cytotoxic CD8 + T cells can effectively kill target cells by producing cytokines, chemokines and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and pre-select potent killer cells are lacking. Human CD8 + T cells can be divided into IFN-γ and IL-2 producing cells. Unbiased RNA-sequencing and proteomics analysis on cytokine-producing fixed cells revealed that IL-2 + T cells produce helper cytokines, and that IFN-γ + T cells produce cytotoxic molecules. IFN-γ + T cells could be identified with the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, the cytotoxic features of CD29 + T cells were maintained during cell culture, suggesting a stable phenotype. Pre-selecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that selecting for CD29 + T cells could boost the anti-tumoral activity of T cell therapeutics.
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Cytotoxic T lymphocytes are major effector cells in response to viral infections and in allograft rejection and are implicated in many other immunological reactions. Efficient induction of cytotoxic activity in these cells in many but not all cases depends upon helper T and antigen-presenting cells so that at least three different cell types have to work together. Here we present an in vitro model for the helper T cell-dependent induction of cytotoxic T lymphocytes which allows the investigation of the collaboration of helper and cytotoxic T cells. First results demonstrate that linkage of helper and killer epitopes on the surface of one antigen-presenting cell is a prerequisite for productive interaction between the two T cells that results in induction of cytolytic activity. T helper 1 and T helper 2 cells are equally efficient. The crucial roles of interleukin-2 and interferon-gamma in this process were confirmed. Activated CD4 cells can influence cytotoxic T lymphocytes in such a way that they produce interferon-gamma independent from recognition of cognate peptide. The possibility of direct T-T contacts mediated by adhesion molecules that promote collaboration of the two cells is discussed.
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Infective influenza virus primes mice and increases at least ten-fold the level of splenic cytotoxic T-memory and precursor cells in comparison with normal mice. Intranasal virus infection or intraperitoneal injection of infective virus results in frequencies of 1-2 x 10(-4) cytotoxic T-cell precursors in spleen as determined by limiting dilution assays. With both types of immunization, T-helper cells amplifying the generation of T-killer cells are limiting, and optimal clone frequencies depend on addition of excess T-helper cells. We find that at least part of the T-helper cells amplifying the generation of cytotoxic T cells are cross reactive for the type A influenza viruses and therefore have a similar virus specificity to type A influenza-specific cytotoxic T cells (tc). Help for T-killer cells can be replaced by supernatants derived from Concanavalin A-stimulated rat spleen cells, but presence of antigen is still required to stimulate the Tc precursor or memory cells before they respond to antigen non-specific T cell-growth factor(s) present in the stimulated rat spleen cell medium.
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Abstract Mixed responder populations, consisting of selected Lyt‐2,3 + cells and unselected T cells from two congenic mouse strains differing in their Lyt‐2,3 alleles, were used to study the role of Lyt‐1,2,3 + cells in the generation of cytotoxic effector cells in vitro . The fact that, under these conditions, all primary alloreactive and H‐2‐restricted killer cells are generated from the unselected T cell population and not from the selected Lyt‐2,3 + subset is demonstrated. Isolated, unsensitized Lyt‐2,3 + cells are able to produce primary alloreactive cytotoxic T lymphocytes (CTL) when incubated with alloantigen alone, but appear to be suppressed in the presence of Lyt‐1,2,3 + cells. In contrast, mixtures of Lyt‐2,3 + cells selected from C 57 BLI6 T cells previously primed to alloantigen in vitro , and unselected T cells from the Lyt‐2,3‐congenic partner after exposure to the same antigen give rise to cytotoxic effector cells which derive mainly from the primed Lyt‐2,3 + cell pool and not from the unselected T cell population. Both populations were able to generate CTL when sensitized separately with the alloantigen. The data suggest that Lyt‐1,2,3 + cells contain all primary precursors for both H‐2‐restricted and alloreactive killer cells, as well as lymphocytes suppressing the formation of cytotoxic effector cells from unsensitized Lyt‐2,3 + cells. The Lyt‐ 2,3 + cell pool most likely contains the secondary CTL precursors. In addition, the same antigen‐primed Lyt‐2,3 + pool contains suppressor cells which inhibit the formation of primary CTL from Lyt‐1,2,3 + cells. The data are discussed with respect to the regulation of cytotoxic responses.
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Lymphokine-activated killer cell
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In East Asia and sub-Saharan Africa, chronic infection is the main cause of the development of hepatocellular carcinoma, an aggressive cancer with low survival rate. Cytotoxic T cell-based immunotherapy is a promising treatment strategy. Here, we investigated the possibility of using HBV-specific CD4+ cytotoxic T cells to eliminate tumor cells. The naturally occurring HBV-specific cytotoxic CD4+ and CD8+ T cells were identified by HBV peptide pool stimulation. We found that in HBV-induced hepatocellular carcinoma patients, the HBV-specific cytotoxic CD4+ T cells and cytotoxic CD8+ T cells were present at similar numbers. But compared to the CD8+ cytotoxic T cells, the CD4+ cytotoxic T cells secreted less cytolytic factors granzyme A (GzmA) and granzyme B (GzmB), and were less effective at eliminating tumor cells. In addition, despite being able to secrete cytolytic factors, CD4+ T cells suppressed the cytotoxicity mediated by CD8+ T cells, even when CD4+ CD25+ regulator T cells were absent. Interestingly, we found that interleukin 10 (IL-10)-secreting Tr1 cells were enriched in the cytotoxic CD4+ T cells. Neutralization of IL-10 abrogated the suppression of CD8+ T cells by CD4+ CD25- T cells. Neither the frequency nor the absolute number of HBV-specific CD4+ cytotoxic T cells were correlated with the clinical outcome of advanced stage hepatocellular carcinoma patients. Together, this study demonstrated that in HBV-related hepatocellular carcinoma, CD4+ T cell-mediated cytotoxicity was present naturally in the host and had the potential to exert antitumor immunity, but its capacity was limited and was associated with immunoregulatory properties.
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Cytotoxic CD8 + T cells can effectively kill target cells by producing cytokines, chemokines, and granzymes. Expression of these effector molecules is however highly divergent, and tools that identify and preselect CD8 + T cells with a cytotoxic expression profile are lacking. Human CD8 + T cells can be divided into IFN-γ– and IL-2–producing cells. Unbiased transcriptomics and proteomics analysis on cytokine-producing fixed CD8 + T cells revealed that IL-2 + cells produce helper cytokines, and that IFN-γ + cells produce cytotoxic molecules. IFN-γ + T cells expressed the surface marker CD29 already prior to stimulation. CD29 also marked T cells with cytotoxic gene expression from different tissues in single-cell RNA-sequencing data. Notably, CD29 + T cells maintained the cytotoxic phenotype during cell culture, suggesting a stable phenotype. Preselecting CD29-expressing MART1 TCR-engineered T cells potentiated the killing of target cells. We therefore propose that CD29 expression can help evaluate and select for potent therapeutic T cell products.
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The T cell lineage is commonly divided into CD4-expressing helper T cells that polarize immune responses through cytokine secretion and CD8-expressing cytotoxic T cells that eliminate infected target cells by virtue of the release of cytotoxic molecules. Recently, a population of CD4+ T cells that conforms to the phenotype of cytotoxic CD8+ T cells has received increased recognition. These cytotoxic CD4+ T cells display constitutive expression of granzyme B and perforin at the protein level and mediate HLA class II-dependent killing of target cells. In humans, this cytotoxic profile is found within the human cytomegalovirus (hCMV)-specific, but not within the influenza- or Epstein-Barr virus-specific CD4+ T cell populations, suggesting that, in particular, hCMV infection induces the formation of cytotoxic CD4+ T cells. We have previously described that the transcription factor Homolog of Blimp-1 in T cells (Hobit) is specifically upregulated in CD45RA+ effector CD8+ T cells that arise after hCMV infection. Here, we describe the expression pattern of Hobit in human CD4+ T cells. We found Hobit expression in cytotoxic CD4+ T cells and accumulation of Hobit+ CD4+ T cells after primary hCMV infection. The Hobit+ CD4+ T cells displayed highly overlapping characteristics with Hobit+ CD8+ T cells, including the expression of cytotoxic molecules, T-bet, and CX3CR1. Interestingly, γδ+ T cells that arise after hCMV infection also upregulate Hobit expression and display a similar effector phenotype as cytotoxic CD4+ and CD8+ T cells. These findings suggest a shared differentiation pathway in CD4+, CD8+, and γδ+ T cells that may involve Hobit-driven acquisition of long-lived cytotoxic effector function.
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