In order to examine the mechanisms by which clonal deletion of autoreactive T cells occurs, a peptide antigen was used to induce deletion of antigen-reactive thymocytes in vivo. Mice transgenic for a T cell receptor (TCR) that reacts to this peptide contain thymocytes that progress from the immature to the mature phenotype. Intraperitoneal administration of the peptide antigen to transgenic mice results in a rapid deletion of the immature CD4+ CD8+ TCRlo thymocytes. Apoptosis of cortical thymocytes can be seen within 20 hours of treatment. These results provide direct evidence for the in vivo role of apoptosis in the development of antigen-induced tolerance.

https://science.sciencemag.org/content/sci/250/4988/1720.full.pdf

Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo

Infection with human immunodeficiency virus (HIV) causes AIDS. As a consequence of the interaction of gp120 envelope with the CD4 receptor molecule expressed by a subset of T lymphocytes and by mononuclear phagocytes (MPs), a second envelope protein (gp41) mediates fusion of the virion membrane with the target membrane. In these events the role of adhesion molecules such as LFA-1 has recently been highlighted. Following viral entry, reverse transcription of the virion-associated RNA and integration of proviral DNA into the host genome are crucial steps in HIV infection, which can lead to expression of high levels of new HIV or to silent infection for indefinite periods, a condition defined as viral latency. Several factors in addition to endogenous viral regulatory proteins have been reported as capable of modulating the state of viral latency and expression in vitro, including the cytokine network that normally modulates immune homeostasis as well as the immune response to inflammatory stimuli. Finally, recent studies have underscored the observation that the CD4+ T lymphocytes are the major reservoir of HIV in the peripheral blood compartment and in the lymphoid tissues, which are characterized by a greater viral burden, whereas in nonlymphoid organs such as the brain and the lung, local infection is predominantly sustained by MPs.

https://www.nejm.org/doi/pdf/10.1056/NEJM199302043280508?listPDF=true

Immunopathogenesis of human immunodeficiency virus infection

In immature thymocytes, T cell receptor for antigen (TCR) mobilization leads to an active T cell suicide process, apoptosis, which is involved in the selection of the T cell repertoire. We have proposed that inappropriate induction of such a cell death program in the mature CD4+ T cell population could account for both early qualitative and late quantitative CD4+ T lymphocyte defects of human immunodeficiency virus (HIV)-infected individuals (Ameisen, J.C., and A. Capron. 1991. Immunol. Today. 4:102). Here, we report that the selective failure of CD4+ T cells from 59 clinically asymptomatic HIV-infected individuals to proliferate in vitro to TCR mobilization by major histocompatibility complex class II-dependent superantigens and to pokeweed mitogen (PWM) is due to an active CD4+ T cell death process, with the biochemical and ultrastructural features of apoptosis. Activation-induced cell death occurred only in the CD4+ T cell population from HIV-infected asymptomatic individuals and was not observed in T cells from any of 58 HIV-seronegative controls, including nine patients with other acute or chronic infectious diseases. Activation-induced CD4+ T cell death was prevented by cycloheximide, cyclosporin A, and a CD28 monoclonal antibody (mAb). The CD28 mAb not only prevented apoptosis but also restored T cell proliferation to stimuli, including PWM, superantigens, and the tetanus and influenza recall antigens. These findings may have implications for the understanding of the pathogenesis of acquired immune deficiency syndrome and for the design of specific therapeutic strategies.

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Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals.

The immunopathogenic mechanisms underlying human immunodeficiency virus (HIV) disease are extremely complex; the disease process is multifactorial with multiple overlapping phases. Viral burden is substantial and viral replication occurs throughout the entire course of HIV infection. Inappropriate immune activation and elevated secretion of certain cytokines compound the pathogenic process. Profound immunosuppression ultimately occurs together with a disruption of the microenvironment of the immune system, which is probably unable to regenerate spontaneously. Thus, therapeutic strategies in HIV disease must not be unidimensional, but rather must be linked to the complex pathogenic components of the disease and must address where feasible each of the recognized pathogenic processes for the possibility of therapeutic intervention.

https://science.sciencemag.org/content/sci/262/5136/1011.full.pdf

Multifactorial nature of human immunodeficiency virus disease: implications for therapy

Cell death is a normal physiological process. Morphological studies have shown that cells that die by physiological mechanisms often undergo characteristic changes termed "apoptosis" or "programmed cell death." Recent work has begun to unravel the molecular mechanisms of these deaths and has shown that one of the primary cell-death pathways is conserved throughout much of evolution. In the nematode Caenorhabditis elegans programmed cell deaths are mediated by a mechanism controlled by the ced-9 gene; in mammals apoptosis can often be inhibited by expression of the bcl-2 gene. The ability of the human BCL2 gene to prevent cell deaths in C. elegans strongly suggests that bcl-2 and ced-9 are homologous genes. Although the process of cell death controlled by bcl-2 can occur in many cell types, there appears to be more than one physiological cell-death mechanism. Targets of cytotoxic T cells and cells deprived of growth factor both exhibit changes characteristic of apoptosis, such as DNA degradation. However, bcl-2 expression protects cells from factor withdrawal but fails to prevent cytotoxic T-cell killing. DNA degradation is, thus, not specific for any one cell-death mechanism. The ability of bcl-2 to protect cells from a wide variety of pathological, as well as physiological, stimuli indicates that many triggers can serve to activate the same suicide pathway, even some thought to cause necrosis, and not physiological cell death.

https://www.pnas.org/content/pnas/90/3/786.full.pdf

Toward an understanding of the molecular mechanisms of physiological cell death.

Herein we have investigated the ability of antigen to induce thymocyte death by apoptosis on the basis that this may be the mechanism for the deletion of autoreactive cells during T cell development. We show that the ability of the bacterial "superantigen" staphylococcal enterotoxin B to cause specific depletion of V beta 8+ cells when added to thymus organ cultures is accompanied by DNA degradation into oligonucleosomal fragments, indicating that depletion involves apoptosis. Our results provide the first direct evidence that antigen-induced apoptosis can be triggered in developing T cells.

Gwynn T. Williams

Papers

Antigen-induced apoptosis in developing T cells: a mechanism for negative selection of the T cell receptor repertoire