Setting the path – How qualitative and quantitative differences in TCR-pMHC interactions regulate T cell immune responses

Editors

Eric Huseby

University of Massachusetts Boston

Dietmar Zehn

Swiss Vaccine Research Institute

Impact

ITK acts as a rheostat for the TCR signaling pathway. While the expression of genes like CD69 and IL-2 is not directly proportional to the signaling input at the TCR, other genes like IRF4 have a graded response where expression continues to increase with higher affinity TCR stimulation. High-affinity antigens increase the duration of TCR binding, increasing the stability of activated Lck and Zap70, which amplifies downstream signaling by creating a larger pool of activated LAT signaling complexes. This creates a larger pool of activated ITK, represented here for simplification without the other signaling components in the pathway. We propose that the calcium signaling pathway is uniquely sensitive to ITK and can provide a mechanism for graded IRF4 expression.

Mini Review

29 February 2016

T Cells and Gene Regulation: The Switching On and Turning Up of Genes after T Cell Receptor Stimulation in CD8 T Cells

James M. Conley

, 1 more and

Leslie J. Berg

Signaling downstream of the T cell receptor (TCR) is directly regulated by the dose and affinity of peptide antigen. The strength of TCR signaling drives a multitude of T cell functions from development to differentiation. CD8 T cells differentiate into a diverse pool of effector and memory cells after activation, a process that is critical for pathogen clearance and is highly regulated by TCR signal strength. T cells rapidly alter their gene expression upon activation. Multiple signaling pathways downstream of the TCR activate transcription factors, which are critical for this process. The dynamics between proximal TCR signaling, transcription factor activation and CD8 T cell function are discussed here. We propose that inducible T cell kinase (ITK) acts as a rheostat for gene expression. This unique regulation of TCR signaling by ITK provides a possible signaling mechanism for the promotion of a diverse T cell repertoire in response to pathogen.

31,277 views

75 citations

Length of interaction alters the activation of specific transcription factors. (A) Schematic diagram denoting the major signaling molecules involved in the T cell activation process upon stimulation of the TCR by cognate pMHCII, leading to the differential activation of downstream transcription factors based on signal strength and interaction times. (B) Short-term interactions induce a subset of default pathway of fast-acting transcription factors, which preferentially activate Th2-associated genes. Interaction for a longer period of time induces both default pathway-associated transcription factors and additionally allows for the induction of Th1-specific transcription factor activation, which are able to override the default Th2-inducing signal and skew the response toward the differentiation of a Th1 subset.

Hypothesis and Theory

25 January 2016

TCR Signal Strength Alters T–DC Activation and Interaction Times and Directs the Outcome of Differentiation

Nicholas van Panhuys

The ability of CD4+ T cells to differentiate into effector subsets underpins their ability to shape the immune response and mediate host protection. During T cell receptor-induced activation of CD4+ T cells, both the quality and quantity of specific activatory peptide/MHC ligands have been shown to control the polarization of naive CD4+ T cells in addition to co-stimulatory and cytokine-based signals. Recently, advances in two-photon microscopy and tetramer-based cell tracking methods have allowed investigators to greatly extend the study of the role of TCR signaling in effector differentiation under in vivo conditions. In this review, we consider data from recent in vivo studies analyzing the role of TCR signal strength in controlling the outcome of CD4+ T cell differentiation and discuss the role of TCR in controlling the critical nature of CD4+ T cell interactions with dendritic cells during activation. We further propose a model whereby TCR signal strength controls the temporal aspects of T–DC interactions and the implications for this in mediating the downstream signaling events, which influence the transcriptional and epigenetic regulation of effector differentiation.

11,113 views

95 citations

Review

16 December 2015

Ubiquitylation as a Rheostat for TCR Signaling: From Targeted Approaches Toward Global Profiling

Claire E. O’Leary

, 1 more and

Paula M. Oliver

5,693 views

15 citations

Review

17 December 2015

Naïve T Cell Homeostasis Regulated by Stress Responses and TCR Signaling

Daisuke Kamimura

, 13 more and

Masaaki Murakami

5,407 views

6 citations

Review

10 December 2015

TCR Signaling in T Cell Memory

Mark A. Daniels

and

Emma Teixeiro

T cell memory plays a critical role in our protection against pathogens and tumors. The antigen and its interaction with the T cell receptor (TCR) is one of the initiating elements that shape T cell memory together with inflammation and costimulation. Over the last decade, several transcription factors and signaling pathways that support memory programing have been identified. However, how TCR signals regulate them is still poorly understood. Recent studies have shown that the biochemical rules that govern T cell memory, strikingly, change depending on the TCR signal strength. Furthermore, TCR signal strength regulates the input of cytokine signaling, including pro-inflammatory cytokines. These highlight how tailoring antigenic signals can improve immune therapeutics. In this review, we focus on how TCR signaling regulates T cell memory and how the quantity and quality of TCR–peptide–MHC interactions impact the multiple fates a T cell can adopt in the memory pool.

14,891 views

90 citations

After interaction with self-peptide on thymic APC, both cells perceive a signal strong enough to guide them safely through positive selection. However, the signal sensed by cell Z is quantitatively or qualitatively stronger, resulting in greater CD5 expression on the mature thymocyte Z, relative to mature thymocyte X. Upon egress from the thymus, these differing CD5 levels are sustained. In the periphery, both naïve T cells are maintained via tonic signaling (i.e., periodic TCR recognition of self-pMHC). Upon initial TCR recognition of the same peptide, cell Z exhibits increased levels of phosphorylated ERK and produces higher amounts of IL-2, relative to cell X. However, by the peak of the immune response, cell X is highly proliferative and capable of generating CD8+ T cell help, whereas cell Z is highly apoptotic and a poor generator of CD8+ T cell help. Some cell Z clones, however, may differentiate into regulatory T cells, due at least in part to their high expression of CD5. During a recall response, memory cell Z now proliferates strongly in response to the same cognate antigen sensed during the primary immune response, while proliferation of cell X is negligible.

Mini Review

11 December 2015

Functional Heterogeneity in CD4+ T Cell Responses Against a Bacterial Pathogen

Ashley Viehmann Milam

and

Paul M. Allen

3,976 views

11 citations

Review

05 November 2015

The Timing of T Cell Priming and Cycling

Reinhard Obst

19,926 views

92 citations

Review

18 November 2015

Identifying Individual T Cell Receptors of Optimal Avidity for Tumor Antigens

Michael Hebeisen

, 4 more and

Nathalie Rufer

12,730 views

75 citations

Random sampling of measured TCR:pMHC reveals rapid approach to average affinity for an entire population. Previous 2D affinity measurements of MOG-specific CD4 T cells were combined and randomly arranged. A moving average was calculated and graphed as a function of the number of cells sampled. Cells were then randomly rearranged and moving average calculations were performed nine more times to generate the curves illustrated.

Review

10 September 2015

Lower Affinity T Cells are Critical Components and Active Participants of the Immune Response

Ryan J. Martinez

and

Brian D. Evavold

Kinetic and biophysical parameters of T cell receptor (TCR) and peptide:MHC (pMHC) interaction define intrinsic factors required for T cell activation and differentiation. Although receptor ligand kinetics are somewhat cumbersome to assess experimentally, TCR:pMHC affinity has been shown to predict peripheral T cell functionality and potential for forming memory. Multimeric forms of pMHC monomers have often been used to provide an indirect readout of higher affinity T cells due to their availability and ease of use while allowing simultaneous definition of other functional and phenotypic characteristics. However, multimeric pMHC reagents have introduced a bias that underestimates the lower affinity components contained in the highly diverse TCR repertoires of all polyclonal T cell responses. Advances in the identification of lower affinity cells have led to the examination of these cells and their contribution to the immune response. In this review, we discuss the identification of high- vs. low-affinity T cells as well as their attributed signaling and functional differences. Lastly, mechanisms are discussed that maintain a diverse range of low- and high-affinity T cells.

11,706 views

68 citations

Intrinsic changes in memory CD4 T cells which enhance their response to activation. There are a number of factors that can contribute to the distinct responses of memory CD4 T cells as compared to their naïve counterparts. T cell receptor (TCR) triggering can be enhanced in two ways: in polyclonal populations, the cells with the highest affinity for the antigen can come to dominate the response (1) alternatively, or in addition, the CD3 TCR-signaling complex is clustered more effectively in memory than naïve CD4 T cells (2). Intracellular signaling molecules are also altered: memory CD4 T cells contain more Zap 70 than naïve T cells (3) and TCR activation leads to increased phosphorylation of the MAPK, p38 (4). Changes in cell surface proteins, such as chemokine receptors (5) and integrins (6), affect cell migration and location enabling memory CD4 T cells to migrate rapidly to inflamed sites or reside permanently in pathogen-targeted tissues. Changes in gene transcription before and following T cell reactivation are also evident. Epigenetic differences between naïve and memory CD4 T cells enable more rapid transcription of effector molecules, such as cytokines, thereby accelerating the control and clearance of pathogens (17, 97–101).

Review

08 September 2015

Development and Function of Protective and Pathologic Memory CD4 T Cells

Shafqat Ahrar Jaigirdar

and

Megan K. L. MacLeod

15,012 views

44 citations

Force initiated TCR signaling. The force generated from the pMHC interaction with the TCR results in allosteric changes within the TCR subunits, most notably in the positioning of the TCR CβFG loop and rearrangement, and impacts the VαVβ module and quaternary αβTCR subunit changes. This restructuring through compression and tension forces (denoted by gray facing or opposing pairs of arrows) may alter the arrangement of the TCR TM domains and co-occur with changes in the membrane lipid composition. The ITAMs are thought to be released from the plasma membrane and become available to tyrosine kinase phosphorylation, thereby initiating T cell activation. Upon TCR–pMHC dissociation, the TCR returns to its initial disengaged state. In the illustration, the CD3ζ cytoplasmic tails are shown to be membrane associated, where the ITAM tyrosine residues are embedded into the membrane and consequently shielded from phosphorylation, as has been observed for the CD3ε cytoplasmic tail (54–58). Other studies have demonstrated that the CD3ζ subunits exist in a constitutively phosphorylated state and therefore would not be associated with the lipid membrane as depicted (59–61) (pMHC, orange; CβFG loop, magenta; TCR complex, other colors; lipid alteration, yellow circle).

Review

03 September 2015

Structural Features of the αβTCR Mechanotransduction Apparatus That Promote pMHC Discrimination

Kristine N. Brazin

, 7 more and

Ellis L. Reinherz

The αβTCR was recently revealed to function as a mechanoreceptor. That is, it leverages mechanical energy generated during immune surveillance and at the immunological synapse to drive biochemical signaling following ligation by a specific foreign peptide–MHC complex (pMHC). Here, we review the structural features that optimize this transmembrane (TM) receptor for mechanotransduction. Specialized adaptations include (1) the CβFG loop region positioned between Vβ and Cβ domains that allosterically gates both dynamic T cell receptor (TCR)–pMHC bond formation and lifetime; (2) the rigid super β-sheet amalgams of heterodimeric CD3εγ and CD3εδ ectodomain components of the αβTCR complex; (3) the αβTCR subunit connecting peptides linking the extracellular and TM segments, particularly the oxidized CxxC motif in each CD3 heterodimeric subunit that facilitates force transfer through the TM segments and surrounding lipid, impacting cytoplasmic tail conformation; and (4) quaternary changes in the αβTCR complex that accompany pMHC ligation under load. How bioforces foster specific αβTCR-based pMHC discrimination and why dynamic bond formation is a primary basis for kinetic proofreading are discussed. We suggest that the details of the molecular rearrangements of individual αβTCR subunit components can be analyzed utilizing a combination of structural biology, single-molecule FRET, optical tweezers, and nanobiology, guided by insightful atomistic molecular dynamic studies. Finally, we review very recent data showing that the pre-TCR complex employs a similar mechanobiology to that of the αβTCR to interact with self-pMHC ligands, impacting early thymic repertoire selection prior to the CD4⁺CD8⁺ double positive thymocyte stage of development.

7,679 views

63 citations