T-cell activation in the intestinal mucosa

Abstract

The vast majority of peripheral T cells exist as resting lymphocytes until a signal for activation has been received. In response to antigen, this activation involves ligation of the T-cell receptor (TCR) and signal transmission through the CD3 complex, which then initiates a cascade of intracellular events that lead to the expression of genes used in T-cell activation. T-cell activation also requires soluble mediators in the form of cytokines and chemokines that regulate the process in both positive and negative ways, and costimulatory signals received in conjunction with TCR/CD3 signaling are important in the activation of T cells. Unlike T cells in other peripheral immune compartments, small and large intestinal intraepithelial lymphocytes (IELs) bear some but not all properties of activated T cells, suggesting that they constitute a large population of 'partially activated' effector cells. Thus, regulation of the IEL activation process must be held in tight check, yet it must be ready to respond to foreign antigen rapidly and effectively. We discuss how costimulatory molecules may hold the key to controlling IEL activation through a multiphase process beginning with cells that have already entered into the early stage of activation.

Fig. 1. CD69 stimulation of murine small intestinal IELs results in the secretion of TGFβ1

Small intestinal IELs from normal C57BL/6 mice were cultured in vitro with 0.1, 1.0, or 10 μg/ml of functional grade anti-CD69 mAb and cell-free supernatants were assayed for TGFβ1 activity after 24 hrs. Note the dose-dependent synthesis of TGFβ1 production following by CD69 stimulation, and the low level of TGFβ1 activity in cultures without stimulation. These findings suggest that the presence of CD69 on intestinal IELs may serve to maintain a level of TGFβ1 that is used to retain those cells in a quiescent, partially-activated state until a signal for full activation has been received.

Fig. 2. Murine small intestinal IELs consist of equivalent proportions of CD43 S7⁺ and S7⁻ cells, with each population consisting of both TCRαβ and TCRγδ IELs

Unlike T cells in other murine peripheral immune compartments, which uniformly express the CD43 neuraminidase-sensitive CD43 S7 determinant, only about half of the IELs are S7⁺ cells. The S7⁺ and S7⁻ IELs display important functional differences as discussed in the article.

Fig. 3. Two-phase model of IEL costimulation involving constitutively-expressed and upregulated costimulatory molecules and receptors

The constitutively-expressed molecules consist of CD43, CD69, CD160, and the IL-18R. CD69, which is acquired on IELs upon entry into the intestinal mucosa, serves to maintain partially-activated (cytotoxic) IELs, through the secretion of low levels of TGFβ1, from entering into a state of full activation until a signal has been received for activation via the TCR/CD3 complex alone, or upon TCR/CD3 stimulation in conjunction with one of the constitutively-expressed costimulatory molecules. Costimulation through CD43 or CD160 leads to enhanced proliferation and/or cytokine synthesis, and overrides the immunosuppressive effects mediated by CD69/TGFβ1. Costimulation of IELs by IL-18, a powerful proinflammatory cytokine, increases both Th1 and Th2 cytokine activities and augments cell-mediated immunity and NK responses. Direct stimulation of IELs via the TCR/CD3 complex in the absence of costimulation results in selective upregulation of CD134, CD137, CD59, and/or CD278, depending upon the type of IEL that has been activated. These will drive the IEL response into a heightened state of activation consisting of greater cell proliferation, enhanced cytotoxicity, and/or the synthesis of regulatory and effector cytokines, while concomitantly overriding the effects of TGFβ1. The immunological consequences of activation through the costimulatory molecules will depend largely upon the IEL subset(s) that expresses them, as delineated in Table 1.