Rise Schwab

The origin and fate of β2m-free MHC class I molecules induced on activated T cells

Abstract We report here that the expression of major histocompatibility complex (MHC) class I heavy chains not associated with β2-microglobulin is induced on resting human T cells by a variety of stimuli. These β2m-free class I heavy chains are not transported as such from the endoplasmic reticulum but originate from surface β2m-associated MHC class I molecules. β2m-free class I heavy chains are spontaneously released from the surface of activated cells. Cross-linking of β2mfree class I heavy chains with specific monoclonal antibodies results in the rapid down-regulation and internalization of these molecules. In contrast, β2m-associated MHC class I molecules display a different pattern of modulation. Previously, we reported that β2m-free class I heavy chains interact with CD8 molecules expressed on the same activated T cells. We propose that interactions between these molecules are involved in a mechanism regulating the function of activated T cells.

Cross-wiring of the immune response in old mice: increased autoantibody response despite reduced antibody response to nominal antigen.

Older humans and experimental animals have been repeatedly found to have higher titers of autoantibodies than do younger individuals despite the impaired responses of older individuals to foreign antigens. The studies reported here were designed to examine the relationship between these two age-related changes in antibody responses. Antibody response to foreign antigen was measured concurrently with autoantibody response in the same mice. Old mice (18-24 months old) had decreased responses to foreign antigens and increased responses to bromelain-treated syngeneic erythrocytes, compared to young mice (2 months old). In vitro mixing experiments were consistent with the possibility that suppressor cell activity in spleen cells from old mice reduce the antibody response to foreign antigen but not to autologous antigen. The results support an emerging view that age-associated changes in immune responses are the result of dysregulation rather than exhaustion of the immune system.

Peritoneal lavage reduces lipopolysaccharide-induced elevation of serum TNF-alpha and IL-6 mortality in mice.

The contribution of peritoneal cells to lipopolysaccharide (LPS)-induced elevation of serum TNF-α and IL-6 levels and mortality has been studied. Peritoneal lavage performed before LPS administration reduced serum cytokine levels by approximately 50% and mortality from 50 to 100%. The effect of peritoneal lavage is due to the removal of peritoneal cells as reinjection of peritoneal cells eliminated the protective effect of lavage on LPS-induced mortality. A special role of peritoneal macrophages in the systemic response to LPS was suggested by the finding that LPS-induced an increase in intracellular TNF-α and IL-6 in peritoneal macrophages but in neither splenic nor bone marrow macrophages. Intraperitoneal injection of thioglycollate broth 4 days prior to lavage increased the number of peritoneal cells removed by lavage and increased protection from LPS mortality. Peritoneal lavage performed 30 to 120 minutes after the LPS administration completely protected all mice from LPS-induced mortality, suggesting the possibility that such treatment may offer a novel therapeutic approach to septic shock.

CD3 pathway of T-cell activation: II. Role of HLA-class I molecules in early events

The role of distinct regions of HLA class I molecules in regulating T-cell activation via the CD3-antigen receptor complex was investigated. Monoclonal antibodies (MoAbs) which recognize monomorphic and polymorphic epitopes on HLA Class I molecules were shown to inhibit T-cell proliferation to OKT3. These MoAbs have differential effects on the synthesis of interleukin-2 (IL-2) and IL-2 receptor expression. Cell cycle analysis demonstrated that these MoAbs function both in inhibiting cell cycle entry (G0-G1 shift) and in blocking cell cycle progression (G1-S shift) of activated T cells. Furthermore, these MoAbs have regulatory effects on the alternate pathway of T-cell activation via the CD2 molecule, T-cell activation induced by PHA, and activation induced by the phorbol ester PMA in conjunction with the calcium ionophore Ionomycin. Thus these MoAbs have different effects depending upon the pathway of T-cell activation. The results indicate that HLA class I molecules are selectively involved in the sequence of intracellular events leading to T-cell activation and proliferation.

Lymphocyte transformation induced by autologous cells. XVII: Lower autologous mixed lymphocyte reaction in subjects with a history of hayfever

The autologous mixed lymphocyte reaction (AMLR) is impaired in patients with a number of diseases associated with abnormal immunoregulation. Since allergic disorders are also associated with abnormal immunoregulation, we assessed the AMLR in individuals with a history of ragweed hayfever. Lymphocytes from allergic subjects had a lower AMLR than nonallergic controls by rank order analysis. These results support the association of abnormal in vivo immunoregulation with reduced AMLR.

Lymphocyte proliferation induced by autologous cells. XV. Relationships between the human autologous mixed lymphocyte reaction stimulated by non-T and activated T cells☆

The human (T:T act) AMLR was characterized in its relationship to the (T:Non-T) AMLR and its validity as a nonxenogeneic antigen induced response was extended. Human T cell lines, established from responding T cells in an autologous mixed lymphocyte reaction (MLR), were maintained in medium containing human serum and interleukin-2 (IL-2). These cells stimulated 3H-thymidine incorporation by autologous T cells and by autologous unfractionated blood mononuclear cells. Freshly activated T cells isolated from an autologous MLR stimulated autologous T cells to a lesser extent could be enhanced by adding IL-2. Twenty-five to 50% of T cells stimulated by activated T cells express the T8 determinant. In contrast, we have previously shown that less than 10% of T cells activated after 6 days in culture with non-T cells express the T8 determinant. The number of T8 bearing cells were increased significantly after 10 days in culture with non-T cells. This suggested that two types of reactions, the (T:Non-T) and (T:T act) AMLR, might occur in sequence when T cells and autologous non-T cells are cocultured: first, the activation of T4 cells by non-T cells, then by the activation of T8 cells by activated T4 cells. Finally, activated T cells can stimulate unfractionated autologous mononuclear cells without prior exposure to sheep erythrocytes or fetal calf serum.

The Clinical Significance of Immune Senescence

It is now 20 years since Walford proposed an immunologic theory of aging (Walford, 1969). According to this theory, changes in the anatomy and physiology of the immune system lead to the alterations in the organism with time that are known as aging. Thus, immune senescence was suggested to be the basic mechanism underlying the process of aging.