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 ...

Regulatory CD4 T cells (Tregs) are defined as FoxP3+ cells and are categorized as natural (nTreg) or induced (iTreg). iTregs can be further classified as pathogen or epitope specific (pTreg). pTregs can share epitope specificity with effector cells (Teffs) and expand in response to infection. Although pTregs reduce infection-induced immunopathology, over-expansion and persistence can have a negative impact on pathogen clearance. Studying CD4 T cell responses to respiratory syncytial virus (RSV) infection, we found that the pTreg response had different dynamics than Teffs, which promoted efficient RSV clearance with minimal immunopathology and effectively established adaptive memory responses. The IA(b)M209-specific pTreg response was subdominant to IA(b)M209-specific Teffs. It peaked early to suppress responses in lymphoid organs after primary infection, but had limited regulation on CD8 T cell responses at the site of infection. The IA(b)M209-specific pTreg response contracted when the specific Teff responses peaked, and was diminished after secondary infection when an adequate adaptive Teff responses were established. The dynamics and differentiation pattern of the IA(b)M209-specific pTreg response was TCR clonotype-specific and enriched for recent thymic immigrants even on secondary infection, which suggests that pTreg responses are recalibrated with each infection to provide an optimal balance of Teff-mediated virus clearance and immunoregulation to limit tissue damage.