From synapses to immunological memory: the role of sustained T cell stimulation

doi:10.1016/S0952-7915(99)00056-4

Current Opinion in Immunology

Volume 12, Issue 1, 1 February 2000, Pages 92-98

https://doi.org/10.1016/S0952-7915(99)00056-4 Get rights and content

Abstract

T cell activation is a sustained process driven by antigen and cytokines, which results in the generation of large numbers of effector and memory cells. Recent experiments from different fields have shed light on the mechanisms that maintain the signaling process at the level of a single synapse between a T cell and an antigen-presenting cell, as well as at the level of a secondary lymphoid organ, in the course of the immune response. These findings explain the unique capacity of the immune system to discriminate between antigens from infectious and noninfectious agents.

Introduction

A fundamental property of the immune system is its capacity to discriminate the context in which antigen is encountered — to mount inflammatory or cytotoxic responses to antigens carried by infectious organisms, while failing to respond in the same way to antigens in the context of normal tissues. Recent progress in the fields of T cell activation and dendritic cell (DC) physiology offer new insights into this fundamental aspect of the immune response. In this review we will first consider the requirements for T cell activation with emphasis on the mechanisms that sustain and amplify TCR signaling. Then we will discuss the process of differentiation of naive T cells to effector and memory cells. Finally, we will consider how stimulation and migration of DCs can provide and sustain the stimuli necessary for T cell activation and differentiation.

Section snippets

Initiation and sustenance of signaling at the immunological synapse

The signals that lead to T cell activation are generated at the synapse between T cells and antigen-presenting cells. At this site, characteristic supramolecular activation complexes (SMACs) are formed. The TCR, MHC molecules, and protein kinase C (PKC)-θ are enriched in a central position, while integrins and the adhesion molecule ICAM-1 form an outer ring around this central structure 1, 2•.

The kinetics of synapse formation have been studied in living cells interacting with planar membranes

Differential requirements for costimulation in naive and activated T cells

Costimulation via CD28 does not affect the extent and kinetics of TCR triggering but amplifies the signaling process in naive T cells and protects activated cells from activation-induced cell death 20, 21. CD28 engagement leads to the recruitment of rafts (that contain Lck and LAT) to the synapse, resulting in more extensive and more stable phosphorylation of multiple substrates and in increased activation and consumption of Lck [22^•]. Naive T cells have low levels of rafts and Lck on their

The role of sustained signaling and cell division in T cell activation and polarization

T cell activation requires sustained signaling to maintain transcription factors such as NF-AT in the nucleus 26, 27. In the presence of high doses of antigen and full costimulation, naive T cells need at least 20 hours of sustained stimulation to increase their size and become committed to proliferation. A longer time of stimulation is required as the dose of antigen or costimulation decreases [21]. In CD28 deficient mice high antigen doses and repeated administrations are required to induce a

Migration, effector function and memory

In differentiating T cells the effector program is intimately linked to the migratory program. Whereas naive T cells express the lymph-node-homing chemokine receptor CCR7 [38^•], effector Th1 and Th2 cells lose CCR7 and express different sets of chemokine receptors that allow them to enter tissues undergoing delayed-type hypersensitivity or allergic reactions [39]. Uncommitted T cells lacking immediate effector function can be expanded from naive T cells under nonpolarizing conditions or in the

T cell stimulation sustained by DC activation and recruitment

The role of DCs as regulators of the T cell response is well established (reviewed in [42^•]). Immature DCs and their precursors, circulating monocytes, migrate from blood to peripheral tissues — where they capture antigen — and from there to the draining lymph nodes, where they arrive as mature stimulatory DCs. The possibility of maintaining DCs in tissue culture in their highly endocytic, poorly stimulatory, immature state has allowed the identification of the stimuli that initiate the

Conclusions

T cell activation has entered a dynamic and exciting era. At the molecular level the dynamics of TCR engagement and triggering are increasingly understood. The serial triggering process allows a kinetic discrimination of ligands and sustains the signaling process, thus driving T cell activation and polarization. At the cellular and systemic level, DC activation and migration play a central role in the regulation of the immune response. DCs use ancient recognition systems characteristic of the

Update

Since the submission of this review, three important papers have been published that are particularly relevant 68•, 69•, 70•.

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

• of special interest
•• of outstanding interest

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The phenotypes of DCs were analyzed by using flow cytometry while phagocytosis was assessed by the uptake of FITC-dextran. Antigen presenting ability to allogeneically naïve or syngeneically primed T lymphocytes was examined by the lymphocyte proliferation of mixed lymphocyte reaction (MLR). In addition, the level of chemokine receptor CCR7 mRNA was determined by RT-PCR.
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ReviewFrom synapses to immunological memory: the role of sustained T cell stimulation

Abstract

Introduction

Section snippets

Initiation and sustenance of signaling at the immunological synapse

Differential requirements for costimulation in naive and activated T cells

The role of sustained signaling and cell division in T cell activation and polarization

Migration, effector function and memory

T cell stimulation sustained by DC activation and recruitment

Conclusions

Update

References and recommended reading

Immunol Today

Immunity

Cell

Immunity

Cell

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Immunity

Cell

Cell

Cell

Cell

Immunity

Selective modulation of protein kinase C-theta during T-cell activation

Nature

Three dimensional segregation of supramolecular activation clusters in T cells

Nature

The immunological synapse: a molecular machine controlling T cell activation

Science

Engagement of T cell receptor triggers its recruitment to low-density detergent-insoluble membrane domains

EMBO J

Aggregation of lipid rafts accompanies signaling via the T cell antigen receptor

J Cell Biol

Serial triggering of many T-cell receptors by a few peptide-MHC complexes

Nature

Sustained signaling leading to T cell activation results from prolonged T cell receptor occupancy. Role of T cell actin cytoskeleton

J Exp Med

The efficiency of antigen recognition by CD8+ CTL clones is determined by the frequency of serial TCR engagement

J Immunol

Serial TCR engagement and down-modulation by peptide:MHC molecule ligands: relationship to the quality of individual TCR signaling events

J Immunol

Quantitative contribution of CD4 and CD8 to T cell antigen receptor serial triggering

J Exp Med

A T cell receptor (TCR) antagonist competitively inhibits serial TCR triggering by low-affinity ligands, but does not affect triggering by high-affinity anti-CD3 antibodies

Eur J Immunol

T cell receptor (TCR) antagonism without a negative signal: evidence from T cell hybridomas expressing two independent TCRs

J Exp Med

Ligand recognition by alpha beta T cell receptors

Annu Rev Immunol

T cell activation determined by T cell receptor number and tunable thresholds

Science

T lymphocyte costimulation mediated by reorganization of membrane microdomains

Science

A receptor/cytoskeletal movement triggered by costimulation during T cell activation

Science

Developmental regulation of Lck targeting to the CD8 coreceptor controls signaling in naive and memory T cells

J Exp Med

Ligand-receptor interactions required for commitment to the activation of the interleukin 2 gene

J Immunol

Review
From synapses to immunological memory: the role of sustained T cell stimulation