Perspectives for Computer Modeling in the Study of T Cell Activation

Abstract

The T cell receptor (TCR) is responsible for discriminating between self-and foreign-derived peptides, translating minute differences in amino-acid sequence into large differences in response. Because of the great variability in the TCR and its ligands, activation of T cells by foreign peptides is a quantitative process, dependent on a mix of upstream signals and downstream integration. Accordingly, quantitative data and computational models have shed light on many important aspects of this process: molecular noise in ligand recognition, spatial dynamics in T cell-APC (antigen presenting cell) interactions, graded versus allor-none decision making by the TCR apparatus, mechanisms of peptide antagonism and synergism, and the tunability and robustness of activation thresholds. Though diverse in their formalism, these studies together paint a picture of how modeling has shaped and will continue to shape understanding of T cell immunobiology.

A new look at T cell receptor signaling to nuclear factor-κB

“…Whereas analog signaling is a graded response that is proportional to stimulus intensity, digital signaling produces an all-or-none response, irrespective of intensity of the activation stimulus [62]. In T cells, increasing TCR stimulation strength leads to an increasing percentage of cells with IκBα phosphorylation and RELA activation, without altering per cell level of the two proteins [63].…”

Cross-Reactivity of T Cells and Its Role in the Immune System

“…106–108 However, which accessory signals might compensate for lower inherent affinity and allow an immune response under sub-optimal conditions has not yet been well elucidated.…”

Affinity and dose of TCR engagement yield proportional enhancer and gene activity in CD4+ T cells

“…These variable responses to ligands of differing affinity are especially interesting in the context of the digital TCR response. TCR responses have been characterized as digital ( Coward et al, 2010 )—that is, signaling downstream of the TCR is either all-on or all-off, such that a given T cell must either be committed to a full response or to no response. Previous work has established this switch-like behavior as observable in terms of extracellular markers such as CD69 ( Das et al, 2009 ; Daniels et al, 2006 ), ERK pathway component localization ( Das et al, 2009 ; Daniels et al, 2006 ; Prasad et al, 2009 ), NF-κB activation ( Kingeter et al, 2010 ), NFAT localization ( Marangoni et al, 2013 ; Podtschaske et al, 2007 ), cell-cycle entry ( Au-Yeung et al, 2014 ), and cytokine production ( Podtschaske et al, 2007 ; Huang et al, 2013 ).…”

“…In particular, AP-1, which comprises homo- or heterodimers assembled from proteins of the Fos, Jun, and ATF transcription factor families ( Murphy et al, 2013 ), requires both TCR and co-stimulatory signaling ( Rincón and Flavell, 1994 ), and it is usually activated by the Ras/Raf/Mek/Erk pathway ( Murphy and Blenis, 2006 ; Schade and Cutting edge, 2004 ). At least four feedback loops have been identified in thymocytes and peripheral T cells downstream of the TCR ( Coward et al, 2010 ; Feinerman et al, 2008 ). Collectively, these feedback loops serve to enforce a digital response by either dampening sub-threshold signaling or amplifying above-threshold signaling, resulting in T cell responses that are all-off or all-on, respectively.…”