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 apparent switch in proliferative T cell reactivity which occurred in a B10 T cell line (B10(T4)) repeatedly stimulated with trinitrobenzene sulfonic acid (hapten)-treated syngeneic cells is described. This functionally heterogenous T cell population, apparently depleted of alloreactivity and strictly dependent on cells expressing syngeneic I-A and the hapten for its propagation, lost, after its 10th restimulation, the previously detected T cell functions, and expressed a new pattern of proliferative reactivity; this pattern included reactivity to self-I-A plus hapten as well as to untreated stimulating cells expressing certain allogeneic determinants. Analysis of reactivity of B10(T4) cells grown under limiting dilution conditions and of five clones of cells derived from B10(T4) indicated that the same T cells were reactive to both self-I-A plus hapten, and to a public I-A-mapped alloantigen possibly related to the serologically defined Ia.5 specificity.

I region-restricted T cell line stimulated with hapten-treated syngeneic cells: selection of clones with reactivity for both allogeneic Ia determinants and self-I-A plus hapten.

Françoise Albert

Papers

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

I region-restricted T cell line stimulated with hapten-treated syngeneic cells: selection of clones with reactivity for both allogeneic Ia determinants and self-I-A plus hapten.