The liver as a site of T-cell apoptosis: graveyard, or killing field?

The liver is a site at which apoptotic CD8+ cells accumulate during the clearance phase of peripheral immune responses. Normal mouse liver contains an unusual mixture of lymphocytes in which natural killer (NK) and NK-T cells are abundant and apoptotic T cells are present, and we interpret these cell populations as, respectively, agents and targets of an intrahepatic T-cell trapping and killing mechanism. In support of this idea, direct perfusion of activated lymphocyte populations through the normal liver results in the selective retention of activated CD8+ T cells. T cells trapped in this manner undergo apoptosis in the liver. This mechanism could explain the importance of the liver in oral tolerance, the phenomenon of tolerance induced by portal vein infusion of antigenic cells, the tolerance to allogeneic liver allografts, and the persistence of some liver pathogens including hepatitis C.

Function and regulation of memory CD4 T cells.

The development of peripheral naive CD4 T cells is dependent on the success of positive selection of immature T cells in the thymus. Only thymocytes that express a T cell receptor (TCR) capable of recognizing self-MHC with low affinity are selected for survival and differentiation into mature naive T cells. Although the TCR of naive T cells has to maintain self-tolerance, it also propagates naive CD4 T cell proliferation on recognition of appropriate foreign peptide associated with MHC class II on antigen-presenting cells (APCs). Naive CD4 T cells that successfully engage foreign peptide undergo further differentiation that leads to the maturation of a select few into the memory T cell pool. Although the requirements that lead to memory T cell development are currently not known, functional changes have been described that are thought to be associated with the greater efficiency with which memory T cells respond to antigen. This article will discuss differences associated with signaling through the TCR of naive and memory CD4 T cells and describe unique control mechanisms imposed on memory CD4 T cells that are likely to have ari sen to counterbalance the altered TCR signaling.

Differential role of CTLA-4 in regulation of resting memory versus naive CD4 T cell activation.

Regulation of peripheral T cell responses is critical for preserving self tolerance. Memory T cells have a lower threshold for activation through the TCR and are thought to be less dependent on costimulation than naive T cells, suggesting a requirement for more stringent regulation of memory T cells. We have recently shown that CD4 engagement apart from the TCR results in the inactivation of memory, but not naive, CD4 T cells. We show here that this inhibition requires ligation of CTLA-4, in that blocking CTLA-4-B7 interactions restores memory CD4 T cell responsiveness. Early signaling through CTLA-4 is possible because resting memory, but not naive, CD4 T cells contain intracellular stores of CTLA-4 that are continuously recycled between the cytoplasm and the cell surface. This mechanism ensures that low intensity TCR engagements, which are thought to be important for peripheral T cell longevity, do not cause memory T cell activation but instead raise their threshold for costimulatory signals. This may give memory T cells an extended lifespan with a reduced risk of inappropriate activation.

Regulation of memory CD4 T cell adhesion by CD4-MHC class II interaction.

CD4 T cell activation requires stable contact with APCs. In the present study we demonstrate that anti-CD3-stimulated memory but not naive CD4 T cells fail to form stable conjugates with MHC class II+ APCs and fail to become activated. Early deconjugation by memory CD4 T cells is dependent on CD4-MHC class II interactions in that conjugation is restored when the APC do not express MHC class II or when the class II molecule is mutated at the CD4 binding site. Furthermore, MHC class II-restricted memory-T cells from CD4-deficient mice form stable conjugates, indicating that the CD4 molecule expressed on naive and memory CD4 T cells differs in function and regulates memory but not naive CD4 T cell adhesion to syngeneic APCs in the absence of Ag. This mechanism may have implications for Ag-primed memory CD4 T cells in that primed memory cells, which express an increased number of adhesion molecules, may dissociate from cells in the absence of CD4/TCR co-ligation by the same MHC class II molecule. This would prevent bystander activation and assure efficient recirculation of activated memory T cells in search of Ag-bearing target cells.

T-cell cytokines in chronic allergic eye disease.

BACKGROUND: The pathophysiology of chronic allergic eye disease cannot be explained by type I hypersensitivity alone, and T cell-mediated inflammation has been strongly implicated as a possible additional mechanism. Previous studies suggested that T(H2)-like T cells play an important role in one form of chronic allergic eye disease. OBJECTIVES: This study examined the cytokine profile of T cells in different clinical groups of subjects with chronic allergic eye disease (i.e., vernal keratoconjunctivitis [VKC], atopic keratoconjunctivitis [AKC], and giant papillary conjunctivitis [GPC]) and normal control subjects. METHODS: In situ hybridization was used to identify cytokine messenger RNA (mRNA), and two-color immunohistochemical analysis was used to demonstrate cytokine immunoreactivity localizing to T cells in the conjunctiva. RESULTS: Allergic tissue expressed increased levels of mRNA for IL-3, IL-4, and IL-5 when compared with normal tissue. There was significantly greater IL-2 mRNA expression in subjects with AKC than in those with VKC (p = 0.004) and those with GPC (p = 0.02). Immunoreactivity for T-cell IL-5 was present more frequently in subjects with VKC (p = 0.004), GPC (p = 0.02), and AKC (p = 0.04) than in normal control subjects. However, T-cell IFN-gamma protein expression was greater in subjects with AKC than in subjects with VKC (p = 0.01), GPC (p = 0.01), and control subjects (p = 0.005). CONCLUSIONS: These results show a T(H2)-like T-cell cytokine array in subjects with VKC and GPC but a shift in cytokine profile toward a T(H1)-like pattern, potentially because of differences in chronicity of the disorders, in subjects with AKC. These important functional T-cell variations in chronic allergic eye conditions are likely to be important in understanding differences in clinical characteristics and therapeutic responses.

Phenotypic characterization of T cells infiltrating the conjunctiva in chronic allergic eye disease.

BACKGROUND: Chronic allergic conjunctivitis comprises a spectrum of diseases including atopic keratoconjunctivitis, atopic blepharoconjunctivitis, vernal keratoconjunctivitis, and contact lens-associated giant pupillary conjunctivitis. Each condition is characterized by a complex immunopathology with a mixed cellular infiltrate. Treatment with conventional mast cell stabilizers is often unsatisfactory, and therapy depends heavily on topical corticosteroids. OBJECTIVE: Recent evidence suggests that T lymphocytes play an important role in mediating the immunopathology seen in the chronic allergic response in the skin and the lungs. METHODS: We have therefore investigated the prevalence of T cells and their subsets in the different chronic allergic eye conditions by means of immunohistochemistry. RESULTS: We found significantly increased numbers of CD4+, CD45RO+, and HLA-DR+ T cells in the conjunctiva of patients with atopic and vernal keratoconjunctivitis and giant papillary conjunctivitis, with a corresponding upregulation of markers present on antigen presenting cells. CONCLUSIONS: These findings suggest that like allergic conditions in the skin and lungs, CD4+ memory T cells are involved in the regulation of the immunopathology of chronic allergic eye responses. Further characterization of these T cells will provide the information necessary for future immunotherapeutic interventions.