Activation and Costimulation of Intestinal T Cells: Independent and Collaborative Involvement of CD43, OX40, and Ly-6C

Abstract

T cells are present in large numbers in the epithelial lining of the small and large intestine of humans and mice. Those cells, referred to as intraepithelial lymphocytes (IELs), are critical for maintaining an effective mucosal immune response against the onslaught of enteric infectious agents and intestinal neoplasia. However, because intestinal immunity must by necessity occur rapidly and efficiently, it is concomitantly important that the local intestinal immune response be curtailed so as not to result in conditions that lead to a destructive inflammatory environment as occurs in inflammatory bowel disease (IBD). Although many aspects of the IEL activation process remain to be understood, emerging evidence indicates that costimulatory molecules on IELs are critical for activation and that they hold the key to regulating intestinal immunity across many levels. In this article, the involvement of three IEL costimulatory molecules (CD43, OX40, and Ly-6C) - working independently or in collaboration-will be discussed in the context of immunity and disease in the human and mouse intestine, and the involvement of those in sustaining the IELs in a uniquely precarious but effective state of activation readiness will be explored.

Fig. (1)

Murine small intestinal IELs express CD69 (A) ex vivo and (B) in situ. (C) Freshly-isolated IELs but not spleen cells are cytotoxic in redirected cytotoxicity assays. (D) following anti-CD3 stimulation in vitro, CD8+ IELs synthesize IFN-γ at higher levels and more rapidly than an equivalent number of CD8+ lymph node cells (LNCs).

Fig. (2)

In fresh IELs preparations, 25–30% of all cells are in the early stage of apoptosis as seen by annexin V staining; this includes some of both TCRαβ and TCRγδ IELs. A very small percentage of the total IELs, generally <3%, are in the late stage of apoptosis as seen by incorporation of both annexin V and propidium iodide.

Fig. (3)

Murine small intestinal IELs constitutively express (A) CD43 but (B) lack expression of the OX40 and Ly-6C costimulatory molecules. Following anti-CD3 stimulation, IELs acquire expression of OX40 and Ly-6C. Direct stimulation of IELs through CD43 in the absence of CD3 stimulation results in the upregulation of Ly-6C but not OX40.

Fig. (4)

In vitro culture of murine small intestinal IELs in the presence of IFN-α induces the expression of Ly-6C but not OX40.

Fig. (5)

Two mechanisms for antigen-independent upregulation of Ly-6C on small intestinal IELs. In the ‘Experimental Model’, based on the findings described in Figs. 3 and 4, expression of Ly-6C can be upregulated either by direct exposure to IFN-α or by direct ligation of CD43. In the ‘Predicted Natural Model’, changes in Ly-6C expression would be manifest following exposure to IFN-α released from nearby virus infected tissue cells. Alternatively, upregulation in Ly-6C expression could occur upon direct engagement of CD43 to its ligand, sialoadhesin [84], on macrophages. The presence of Ly-6C expression on IELs would result in TCR-independent IEL proliferation and IL-2 synthesis upon binding to the Ly-6C ligand that is expressed on B cells or CD11b+ cells [85]; both types of cells are present in the small intestine epithelium.