High frequency of herpesvirus-specific clonotypes in the human T cell repertoire can remain stable over decades with minimal turnover.

High-throughput T cell receptor sequencing on sequentially banked blood samples from healthy individuals has shown that high-frequency clonotypes can remain relatively stable for up to 18 years, with minimal inflation, deflation, or turnover. These populations included T cell expansions specific for Epstein-Barr virus. Thus, in spite of exposure to a barrage of microorganisms over the course of life, the dominant clonotypes in the mature peripheral T cell repertoire can alter surprisingly little.

Apoptosis of inflammatory cells in immune control of the nervous system: role of glia.

The elimination of inflammatory cells within the central nervous system (CNS) by apoptosis plays an important role in protecting the CNS from immune-mediated damage. T cells, B cells, macrophages, and microglia all undergo apoptosis in the CNS. The apoptotic elimination of CNS-reactive T cells is particularly important, as these cells can recruit and activate other inflammatory cells. T-cell apoptosis contributes to the resolution of CNS inflammation and clinical recovery from attacks of experimental autoimmune encephalomyelitis (EAE), an animal model of the demyelinating disease multiple sclerosis (MS). T-cell apoptosis in the CNS in EAE occurs in both an antigen-specific and an antigen-nonspecific manner. In antigen-specific T-cell apoptosis, it is proposed that T cells that recognize their antigen in the CNS, such as CNS-reactive T cells, are deleted by the process of activation-induced apoptosis after activation of the T-cell receptor. This may result from the ligation of T-cell death receptors (such as CD95 (Fas) or tumor necrosis factor (TNF) receptor 1) by CD95 ligand (CD95L) or TNF expressed by the same T cell or possibly by microglia, astrocytes or neurons. Inadequate costimulation of the T cell by antigen-presenting glial cells may render T cells susceptible to activation-induced apoptosis. T cells expressing CD95 may also die in an antigen-nonspecific manner after interacting with glial cells expressing CD95L. Other mechanisms for antigen-nonspecific T-cell apoptosis include the endogenous release of glucocorticosteroids, deprivation of interleukin-2, and the release of nitric oxide by macrophages or glia. Apoptosis of autoreactive T cells in the CNS is likely to be important in preventing the development of autoimmune CNS diseases such as MS.

Carcinogen-modified dendritic cells induce immunosuppression by incomplete T-cell activation resulting from impaired antigen uptake and reduced CD86 expression.

Exposure of the skin to environmental stimuli, such as chemical or physical carcinogens, modifies the local skin environment, including depletion of epidermal Langerhans' cells (LC). Any subsequent exposure of the LC-depleted skin to antigen results in the generation of antigen-specific tolerance. In this study we evaluated the antigen-bearing cells in the draining lymph nodes by capitalizing on the fluorescent nature of the contact sensitizer, fluorescein isothiocyanate (FITC). When FITC was applied to the skin of normal mice, two distinct populations of antigen-bearing cells were identified in the draining lymph nodes. They were classified as either FITChi or FITClo on the basis of their fluorescence intensity and thus the amount of antigen they internalized. Only FITClo cells were detected in the lymph nodes draining FITC-treated murine skin that had been depleted of epidermal LC by prior treatment with the complete carcinogen 9,10-dimethyl 1,2-benzanthracene (DMBA). Functional analysis of these cells revealed that the FITChi cells, but not the FITClo cells, induced antigen-specific T-cell proliferation. Further analysis of the FITClo cells from the DMBA-treated mice demonstrated that these cells had reduced levels of CD80 expression, had substantially reduced levels of CD86 expression and performed poorly as co-stimulator cells in an anti-CD3-mediated proliferative assay. Nonetheless these cells still induced early signs of T-cell activation and interleukin-12 production. Consequently the FITClo cells migrating from the LC-depleted skin, through a combination of reduced antigen presentation and reduced co-stimulatory activity, induced a state of unresponsiveness or anergy in the responder T cells in a similar manner to that observed when antigen presentation occurs in the absence of co-stimulation. We propose that these unresponsive, or anergic cells, account for the antigen-specific tolerance observed in these experiments.