Clonotype‐specific avidity influences the dynamics and hierarchy of virus‐specific regulatory and effector CD4⁺T‐cell responses

Abstract

Th17 (IL-17) cells that produce characteristic cytokines [2], T follicular helper (Tfh) cells that promote B cell differentiation[3] and regulatory T (Treg) cells that express transcription factor FoxP3 and regulate effector T-cell responses [4,5]. Interactions of the peptide-MHC (pMHC) complexes with T-cell receptors (TCRs) and subsequent signaling events play an important role in the fate of CD4 + T cells and influence differentiation into functionally distinct CD4 + T-cell subsets [6]. TCR ligation and the presence of particular cytokine environments lead naïve CD4 + T cells to express signature transcription factors and produce hallmark cytokines. In addition, strong signaling mediated by high avidity TCR interactions induces robust proliferation and effectorPublished 2014. This article is a U.S. Government work and is in the public domain in the USA. www.eji-journal.eu Eur. J. Immunol. 2014. 44: 1058-1068 Immunity to infection 1059 cytokine production, while weak signaling mediated by low avidity TCR generally induces limited clonal expansion [7,8]. T cells expressing low avidity TCR have a disadvantage in interclonal competition and restricted access to pathogen epitopes, and thus are less likely to expand into a functionally distinct population when high avidity T clones are present [9,10]. Maintaining a functional Treg-cell population and the balance of effector and regulatory functions is important for recognition and clearance of virus-infected cells with minimal immunopathology and establishment of immunological memory against subsequent infection [11][12][13]. Treg cells have been shown to limit pulmonary inflammation and lung injury induced by pneumocystis infection [14] and to modulate herpes simplex virus-induced inflammatory lesions of the eye [15]. Natural Treg cells reduce the symptoms of West Nile virus infections in both humans and mice, and Treg cell-deficient mice are more likely to develop lethal infection [16]. In addition, Treg cells suppress autoreactive responses and maintain homeostasis of immunocompetent cells to self-antigens [17,18]. Regulatory functions of the Treg cells can also compromise adaptive immune responses and diminish the control of systemic infections [19], delay virus clearance [20], and interfere with immune surveillance of malignant mutations [21]. In RSV-infected mice, Treg cells have been shown to expand during primary infection [22,23] and influence the hierarchy of T-cell responses [22] and immunopathology [24]. The expanded Treg-cell population maintains an environment that can achieve viral clearance while diminishing disease. Depletion of Treg cells enhances virus clearance but also facilitated CD8 + T-cell response-mediated pathogenic inflammation [22,23,25]. Conversely, increasing Treg-cell frequency by administrating IL-2/anti-IL-2 complex reduced lung inflammation without suppressing virus clearance [26]. A diminished Treg-cell response has been observed in response to a secondary exposure to RSV antigens [27]. While the diminished Treg-cell response was ...

Identification of Novel Respiratory Syncytial Virus CD4+ and CD8+ T Cell Epitopes in C57BL/6 Mice

“…3C). These results are similar to the TCR repertoires of previously defined epitopes M 209-223 and M2-1 [26][27][28][29][30][31][32][33][34][35][36][37][38][39] , which are also highly represented by Vb8.1/8.2-expressing cells (25).…”

Memory of Inflammation in Regulatory T Cells

“…Consistently, Treg TCRs exhibit heightened self-reactivity compared to conventional CD4 T cells. While recognition of non-self antigens may contribute to Treg cell activation in certain settings (Liu et al, 2014; Shafiani et al, 2013), it is not clear if TCR-mediated activation is always the sole driver of Treg cell responses. Consistently, TCR-dependent genes account for only a quarter of the activated Treg cell-specific gene signature (Levine et al, 2014).…”

The role of Th17 and Treg responses in the pathogenesis of RSV infection

“…This was related to the increased disease severity in the setting of prior FI-RSV vaccination, while this relation was not seen upon secondary exposure to natural RSV infection (42). In a study by Wang et al (43), an asthmatic phenotype was induced by sensitizing mice to ovalbumin, resulting in an increased Th17 response and a defective Treg response leading to Th2-mediated airway inflammation.…”