Reversal of airway hyperresponsiveness by induction of airway mucosal CD4+CD25+ regulatory T cells

Abstract

An important feature of atopic asthma is the T cell–driven late phase reaction involving transient bronchoconstriction followed by development of airways hyperresponsiveness (AHR). Using a unique rat asthma model we recently showed that the onset and duration of the aeroallergen-induced airway mucosal T cell activation response in sensitized rats is determined by the kinetics of functional maturation of resident airway mucosal dendritic cells (AMDCs) mediated by cognate interactions with CD4+ T helper memory cells. The study below extends these investigations to chronic aeroallergen exposure. We demonstrate that prevention of ensuing cycles of T cell activation and resultant AHR during chronic exposure of sensitized rats to allergen aerosols is mediated by CD4+CD25+Foxp3+LAG3+ CTLA+CD45RC+ T cells which appear in the airway mucosa and regional lymph nodes within 24 h of initiation of exposure, and inhibit subsequent Th-mediated upregulation of AMDC functions. These cells exhibit potent regulatory T (T reg) cell activity in both in vivo and ex vivo assay systems. The maintenance of protective T reg activity is absolutely dependent on continuing allergen stimulation, as interruption of exposure leads to waning of T reg activity and reemergence of sensitivity to aeroallergen exposure manifesting as AMDC/T cell upregulation and resurgence of T helper 2 cytokine expression, airways eosinophilia, and AHR.

Different Proliferative Potential and Migratory Characteristics of Human CD4+ Regulatory T Cells That Express either CD45RA or CD45RO

“…It is of interest that the proportion of Tregs in the skin increases with age and can contribute to reduced immune responses observed in elderly individuals (18). Although we were not able to examine this, other human tissues, such as gut and lung, also reportedly contain significant numbers of Tregs (45,46). From the available, data it appears that Tregs in these peripheral tissues also display a memory phenotype (31,32,47).…”

CD4+ cells are required for chronic eosinophilic lung inflammation but not airway remodeling

“…CD4ϩCD25ϩFoxp3ϩ Tregs generally represent 5-15% of the total CD4ϩ population in a mouse, and CD4 depletion will eliminate these cells as well. A study in OVAsensitized rats revealed that CD25ϩ ␣␤T cells in the tracheal mucosa begin to increase after the first intranasal challenge of OVA and remained elevated after 10 daily challenges (36). These cells were able to suppress OVA-specific T cell proliferation ex vivo.…”

The role of dendritic cells and regulatory T cells in the regulation of allergic asthma

“…Kearley et al (2005) (Strickland et al, 2006). A major strength of this study was the use of a sensitive and highly accurate technique for determination of airway mechanics separately in the airways and tissue parenchyma (LFOT).…”

“…Naturally occurring Treg cells were traditionally described to be thymically-derived with the function of maintaining systemic homeostasis to control total lymphocyte numbers in order to protect the integrity of tissues and organs in vivo (Sakaguchi et al, 2001). More recently, Treg populations have been induced in vitro and in vivo via culturing with cytokines or in mouse models via pathogenic or allergenic stimulation (Verhasselt et al, 2004;Kretschmer et al, 2005;Luo et al, 2005;Skapenko et al, 2005;Moo-Young et al, 2006;Nicolson & Wraith, 2006;Strickland et al, 2006). The induced Treg populations also have the ability to control other lymphocytes in vivo however they differ from naturally occurring Treg in a number of ways which will be discussed below.…”

“…An induced population of Treg cells (CD4 + 25 high foxP3 + ) has been reported to inhibit the development of AHR in animal models of allergic airways disease (Kearley et al, 2005;Strickland et al, 2006;Joetham et al, 2007). Kearley et al (2005) (Strickland et al, 2006).…”