Protein kinase C, an enzyme that is activated by the receptor-mediated hydrolysis of inositol phospholipids, relays information in the form of a variety of extracellular signals across the membrane to regulate many Ca2+-dependent processes. At an early phase of cellular responses, the enzyme appears to have a dual effect, providing positive forward as well as negative feedback controls over various steps of its own and other signaling pathways, such as the receptors that are coupled to inositol phospholipid hydrolysis and those of some growth factors. In biological systems, a positive signal is frequently followed by immediate negative feedback regulation. Such a novel role of this protein kinase system seems to give a logical basis for clarifying the biochemical mechanism of signal transduction, and to add a new dimension essential to our understanding of cell-to-cell communication.

https://science.sciencemag.org/content/sci/233/4761/305.full.pdf

Studies and perspectives of protein kinase C

T lymphocytes respond to foreign antigens both by producing protein effector molecules known as lymphokines and by multiplying. Complete activation requires two signaling events, one through the antigen-specific receptor and one through the receptor for a costimulatory molecule. In the absence of the latter signal, the T cell makes only a partial response and, more importantly, enters an unresponsive state known as clonal anergy in which the T cell is incapable of producing its own growth hormone, interleukin-2, on restimulation. Our current understanding at the molecular level of this modulatory process and its relevance to T cell tolerance are reviewed.

http://science.sciencemag.org/content/sci/248/4961/1349.full.pdf

A cell culture model for T lymphocyte clonal anergy

We examined the regulation of virus-specific CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. Our study shows that within the same persistently infected host, different mechanisms can operate to silence antiviral T cell responses; CD8 T cells specific to one dominant viral epitope were deleted, whereas CD8 T cells responding to another dominant epitope persisted indefinitely. These virus-specific CD8 T cells expressed activation markers (CD69hi, CD44hi, CD62Llo) and proliferated in vivo but were unable to elaborate any antiviral effector functions. This unresponsive phenotype was more pronounced under conditions of CD4 T cell deficiency, highlighting the importance of CD8– CD4 T cell collaboration in controlling persistent infections. Importantly, in the presence of CD4 T cell help, adequate CD8 effector activity was maintained and the chronic viral infection eventually resolved. The persistence of activated virus-specific CD8 T cells without effector function reveals a novel mechanism for silencing antiviral immune responses and also offers new possibilities for enhancing CD8 T cell immunity in chronically infected hosts.

https://rupress.org/jem/article-pdf/188/12/2205/1117308/98-1509.pdf

Viral Immune Evasion Due to Persistence of Activated T Cells Without Effector Function

Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired.

https://www.cell.com/cell/pdf/0092-8674(92)90428-F.pdf

Genetic evidence for the involvement of the lck tyrosine kinase in signal transduction through the T cell antigen receptor.

Although it has been proposed that the activation of T lymphocytes is mediated by an early rise in cytosolic calcium concentration, it has not been possible to mimic antigen- or mitogen-induced mouse lymphocyte activation by calcium ionophores that bypass receptor-mediated processes. There is now evidence from other systems that the rise in cytosolic calcium which follows receptor triggering is preceded by the breakdown of phosphatidylinositol bisphosphate into 1,2-diacylglycerol and inositol trisphosphate. The latter is known to cause release of calcium from intracellular stores. The cellular target for the former is now widely accepted to be protein kinase C. Therefore, ligand-induced cellular response follows a rise in cytosolic calcium concentration and protein kinase C activation. Here we confirm that the calcium ionophores A23187 and ionomycin do not activate mouse T lymphocytes. However, either one in combination with the phorbol ester 12-O-tetradecanoylphorbol 13-acetate (TPA), which is structurally related to 1,2-diacylglycerol, induces in lymphoid cell populations the expression of receptors for interleukin-2 (IL-2), the secretion of IL-2 and cell proliferation as measured by 3H-thymidine uptake. The growth-promoting effect of IL-2 on an exogenous IL-2-dependent clone could not be substituted for by ionomycin either alone or with TPA. Thus, the combination of calcium ionophores and TPA bypasses the requirement for antigen- or lectin-induced signal at the onset of lymphocyte activation.

Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester

The use of specific T helper cells (TH) has allowed the detection of anti-hapten plus self cytotoxic T-lymphocyte (CTL) precursors in cell populations unable to generate autonomous reactions (and considered as 'immature'). This led us to reevaluate the ontogeny of CTL precursors in different tissues in the presence of adult TH. It was found that thymocytes from newborn mice contained levels of CTL precursors comparable to those of adults and were dependent on TH throughout the donor's life. In the spleens, however, 3 periods could be distinguished: (a) from birth to 4 days after birth, no CTL precursors could be detected even in the presence of TH; (b) from the 5th day to the 2nd week after birth, CTL responses could be obtained only in the presence of TH; (c) after the 2nd week, autonomous responses could be obtained. No evidence for a suppressive mechanism was found in the spleen of the newborn mice, nor could lack of responsiveness be attributed to newborn accessory-cell malfunction. The data indicate that a limiting cell in the development of anti-hapten plus self CTL is the TH from the 4th to the 16th day after birth. The absence of CTL precursors in the spleen, but not in the thymus of neonates would indicate differential T-cell maturation in the two organs or late migration to the spleen.

Ontogeny of anti-self-trinitrophenyl cytotoxic T-cell responses.

Structural changes in class I MHC molecules influencing recognition by allo- or self + TNP-reactive cytotoxic T-cell clones and by monoclonal antibodies.

An immune response induced by the presentation of the hapten trinitrophenyl (TNP) on syngeneic cells can result from in vitro stimulation of T cells with syngeneic cells after trinitrobenzenesulfonate (TNBS) treatment (1) or after TNP-protein adsorption (2), or in vivo by trinitrochlorobenzene (TNCB) skin sensitization (3,4). The heterogeneity of T cell functions (5–9) is evident from the description of effector cells, including cytotoxic T cells (CTL) (1,2,4), helper T cells (TH) for CTL precursors (pCTL) (5) or B cells (6,7), as well as suppressor cells (Ts) (8–10) and delayed-type hypersensitivity (DTH) effector cells (3). In terms of the fine specificity of the response to TNBS-treated cells, it was not clear whether the apparently non-major histo-compatibility complex (MHC) -restricted components of CTL responses in mice (11,12) and humans (13) could originate from T cell recognition of non-MHC and/or nonpolymorphic cell surface antigens (13) in addition to the recognition of the known class I MHC antigens. In order to analyse such a heterogenous response in terms of functional T cell subsets (14,15) and fine specificity of T cells (16,17) we established T cells lines proliferating in response to TNBS-treated syngeneic cells (14) in which we analysed interacting T cell populations (15) and from which we derived individual T cell clones (15–17). The study of the mechanism of action of TH for the development of CTL from thymic precursor cells (5,18) led us to hope that T cell hybridomas might help in the analysis of products secreted by such TH (18). Here we will briefly summarize results obtained with such procedures.

Analysis of the anti-self + TNP immune response: T cell lines, clones and hybridomas.

Studies on T helper cells and the specificity of their soluble products for induction of cytotoxic T cells directed against trinitrophenyl-modified self

Schmitt-Verhulst Am

Papers

Early steps of lymphocyte activation bypassed by synergy between calcium ionophores and phorbol ester

Ontogeny of anti-self-trinitrophenyl cytotoxic T-cell responses.

Structural changes in class I MHC molecules influencing recognition by allo- or self + TNP-reactive cytotoxic T-cell clones and by monoclonal antibodies.

Analysis of the anti-self + TNP immune response: T cell lines, clones and hybridomas.

Studies on T helper cells and the specificity of their soluble products for induction of cytotoxic T cells directed against trinitrophenyl-modified self