Effector functions in the immune system are carried out by a variety of cell types, and as our understanding of the complexity of the system expands, the number of recognized subdivisions of cell types also continues to increase. B lymphocytes, producing antibody, were initially distinguished from T lymphocytes, which provide help for B cells (1, 2). The T-cell population was further divided when surface markers allowed separation of helper cells from cytotoxic cells (3). Although there were persistent reports of heterogeneity in the helper T-cell compartment (reviewed below), only relatively recently were distinct types of helper cells resolved. In this review we describe the differences between two types of cloned helper T cells, defined primarily by differences in the pattern of lymphokines ynthesized, and we also discuss the different functions of the two types of cells and their lymphokines. Patterns of lymphokine synthesis are convenient and explicit markers to describe T-cell subclass differences, and evidence increases that many of the functions of helper T cells are predicted by the functions of the lymphokines that they synthesize after activation by antigen and presenting cells. The separation of many mouse helper T-cell clones into these two distinct types is now well established, but their origin in normal T-cell populations is still not clear. Further divisions of helper T cells may have to be recognized before a complete picture of helper T-cell function can be obtained.

TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties.

Publisher Summary Because cytokine functions are complex and overlapping, the development of precise, monospecific bioassays, and enzyme-linked immunosorbent assays (ELISAs) was essential, before a clear picture of T cell cytokine synthesis could be obtained. In vitro , some mast cell lines synthesize IL-4 and other cytokines of the Th2 pattern in response to cross-linking of surface IgE. Although functional evidence using mixed cell populations suggested different types of Th cells, the lack of discriminatory cell-surface markers has hampered efforts to define the different subtypes. The development of in vitro T cell clones led to the description of four types of helper T cell clones, and later, two types of Th clones (Th1 and Th2) were defined on the basis of different patterns of cytokine secretion. These patterns have been confirmed in several panels of Th clones and this is currently the most clear-cut criterion for separation of mouse Th subtypes. As the two types differ in the synthesis of many cytokines, and the cytokines have a major role in the regulation of immune responses, the two types of Th cells have markedly different functions. When injected simultaneously with antigen into the footpads of naive mice, Th1 clones cause an antigen-specific and major histocompatibility complex (MHC)-restricted inflammatory reaction that peaks at about 24 hours. Th2 clones do not produce a swelling reaction under these conditions. One of the major functions of helper T cells is to provide signals for activation, proliferation, and differentiation to B cells that have encountered an antigen. Several strategies have been employed for studying the functions of mouse Th clones in micro and for analyzing the roles of specific Th products in these functions. In spite of the clear dichotomy of mouse Th1 and Th2 clones, and the accumulating evidence for their involvement in normal immune responses, human T cells do not appear to segregate into two clear subsets. Many human T cell clones secrete both Th1and Th2 cytokines.

Heterogeneity of cytokine secretion patterns and functions of helper T cells.

Studies of cell-surface molecules involved in human T cell interaction reveal that differential expression of each of three adhesion molecules (LFA-3, CD2, and LFA-1) subdivides human peripheral blood T cells into major subpopulations. Systematic analysis of the relationship between expression of these and other markers of T cell subsets demonstrates a single major subset of human peripheral blood T lymphocytes distinguished by enhanced expression of LFA-3, CD2, LFA-1, and three other markers (CDw29 [4B4], UCHL1, and Pgp-1). Large differences in relative expression are observed for UCHL1 (29-fold) and LFA-3 (greater than 8-fold), and smaller differences (2- to 4-fold) are seen for CDw29, CD2, LFA-1, and Pgp-1. Bimodal distribution of LFA-3 is found on both CD4+ cells and on CD8+ cells as well as on B lymphocytes (CD19+). Neonatal T cells (CD3+) are comprised almost exclusively of the subset expressing low LFA-3, CD2, LFA-1, CDw29, and UCHL1. Activation of cord peripheral blood mononuclear leukocytes with PHA leads to uniform enhanced expression of each of these molecules on CD3+ cells. Functional analyses of these T cell subsets were performed after sorting of adult T cells based on differential LFA-3 expression. Only the LFA-3+ subset proliferated in response to the Ag tetanus toxoid, even though the LFA-3- subset proliferated more strongly to PHA. Furthermore, the LFA-3+ subset made greater than fivefold more IFN-gamma than the LFA-3- subset in response to PHA, despite the fact that both subsets made equivalent amounts of IL-2. This phenotypic and functional analysis of resting and activated newborn and adult T cells indicates that human memory T cells express enhanced levels of LFA-3, CD2, LFA-1, UCHL1, CDw29, and Pgp-1; we speculate that the increase in expression of T cell adhesion molecules LFA-3, CD2, and LFA-1 on memory cells is functionally important in their enhanced responsiveness.

Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-gamma production.

Fifty-eight patients with severe, progressive multiple sclerosis were prospectively randomized to one of three treatments: 20 received intravenous ACTH, 20 received high-dose intravenous cyclophosphamide plus ACTH, and 18 were placed on a regimen consisting of plasma exchange, low-dose oral cyclophosphamide, and ACTH. The three groups were similar in age, sex, duration and type of disease, and degree of disability. Before treatment and six months and one year after treatment, a disability-status score, ambulation index, and functional-status score were determined, and a quantitative neurologic examination was performed. In the ACTH group, the number of patients stabilized or improved was 8 of 20 at six months and 4 of 20 at one year; in the cyclophosphamide-ACTH group, 18 of 20 at six months and 16 of 20 at one year; and in the plasma exchange group, 11 of 18 at six months and 9 of 18 at one year. High-dose cyclophosphamide plus ACTH was most effective in halting progression of the disease at bot...

Intensive immunosuppression in progressive multiple sclerosis. A randomized, three-arm study of high-dose intravenous cyclophosphamide, plasma exchange, and ACTH.

Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets

Immunization of mice with lower primate lymphoid cells has provided a useful strategy for raising monoclonal antibodies against functionally important surface determinants on human T lymphocytes. We have developed a monoclonal antibody, anti-2H4, which defines functionally unique human T cell subsets. This anti-2H4 antibody was reactive with approximately 42% of unfractionated T cells, 41% of T4+ inducer cells, and was reactive with approximately 54% of T8+ cytotoxic/suppressor population. Anti-2H4 was not reactive with human thymocytes, but reacted with subsets of peripheral blood B cells and null cells. This antibody subdivided peripheral blood T4+ cells into two functionally distinct populations. The T4+2H4+ subset proliferate well to concanavalin A (Con A) stimulation, but poorly to soluble antigen stimulation, and provides poor help to B cells for PWM-induced Ig synthesis. The T4+2H4- subset, in contrast, proliferates poorly upon stimulation with Con A, but well on exposure to soluble antigen, and provides a good helper signal for PWM-induced Ig synthesis. What is, perhaps, most important, the T4+2H4+ subset functions as the inducer of the T8+ suppressor cells. Previous attempts to define the latter subset of cells has relied heavily on the use of specific autoantibodies present in the sera of patients with juvenile rheumatoid arthritis (JRA) and systemic lupus erythematosus (SLE). The present results suggest that anti-2H4 antibody defines the human suppressor induced subset of lymphocyte previously described as T4+JRA+. Last, the results reemphasize the previously documented remarkable structural conservation of certain T cell-specific determinants on lymphocytes of phylogenetically distant primates.

The isolation and characterization of the human suppressor inducer T cell subset.

To determine whether abnormalities of immunoregulatory T cells are associated with multiple sclerosis (MS), we characterized peripheral lymphocytes in 33 patients with untreated MS and compared them with 42 normal persons and 29 age-matched control subjects who had other neurologic diseases. For this analysis, we used monoclonal antibodies to the surface antigens of helper (T4) and suppressor (T5) T-cell subsets and to a common T-cell antigen (T3). In contract to normal persons and the controls with other neurologic diseases, the patients with MS had a reduced percentage of T3-positive (T3+) cells (P less than 0.05). More importantly, there was a selective decrease in T5-positive (T5+) cells in 11 of 15 patients with active MS, but in only one of 18 patients with inactive MS and in none of the normal persons or controls with neurologic disease (P less than 0.00001). Serial analysis of five patients with MS showed a correlation between the absence of the T5+ subset and disease activity. Thus, there is loss of peripheral suppressor cells in many patients with active MS, suggesting that immunoregulatory abnormalities contribute to the pathogenesis of the disease.

https://www.nejm.org/doi/pdf/10.1056/NEJM198007173030303?listPDF=true

Loss of suppressor T cells in active multiple sclerosis. Analysis with monoclonal antibodies.

Previous studies have shown that patients with systemic lupus erythematosus (SLE) had differing T cell T4+/T8+ ratios and that the ratio correlated with clinical features of the disease. In the present study, we wished to determine whether the peripheral blood T cell subsets in these patients were related to the specificity of anti-T cell antibodies found in their plasma. Plasma from 24 SLE patients that reacted with greater than 20% of normal T cells were analyzed for their effect on in vitro pokeweed mitogen-stimulated immunoglobulin synthesis and for their reactivity with human T4+ and T8+ cells. Anti-T cell antibodies found in SLE patients have a spectrum of reactivities. We concentrated upon antibodies that interfere with suppressor function. One group of SLE anti-T cell antibodies reacts preferentially with the T8+ suppressor effector cell whereas another is reactive with T4+ suppressor inducer subsets. SLE patients with high T4+/T8+ ratios had anti-T cell antibodies predominantly reactive with the T8+ suppressor effector cells. Patients with low T4+/T8+ ratios, on the other hand, had anti-T cell antibodies reactive with either the T4+ suppressor inducer or with both the T4+ suppressor inducer and T8+ suppressor effector cells. In addition, a fourth group was defined whose anti-T cell antibodies were neither reactive with a functional T4+ suppressor inducer nor a functional T8+ suppressor effector cells. There was a significant correlation between the circulating T4+/T8+ ratio of peripheral T cells in these patients and the relative ability of their anti-T cell antibodies to kill T8+ cells vs. T4+ cells (gamma = 0.666, P less than 0.001). These results support the notion that in SLE different cellular defects in the immunoregulatory circuit underlie the development of autoimmune reactions and that the anti-T cell antibodies may cause numerical and functional deficiencies in T cell subsets.

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Relationship between systemic lupus erythematosus T cell subsets, anti-T cell antibodies, and T cell functions.

The cellular interactions necessary for generation of human T suppressor effector function were examined in a primary in vitro antigen-specific anti-DNP antibody-forming system. During the induction of the anti-DNP response, it was found that T cells of both T4+ and T8+ subsets were necessary to suppress antibody formation, whereas after activation, only the T8+ subset was required. Thus, a population of T4+ T cells appears to be necessary to activate or induce a subset of T8+ cells to suppress. The T4+ suppressor inducer population, like the resting or activated T8+ suppressor effector subset, was sensitive to low dose irradiation. Moreover, the radiosensitive T4+ subset and the previously defined T4+JRA+ subset were shown to be functionally similar or complementary in that both were required for generation of suppressor effector function. These findings suggest that T-T interactions between radiosensitive T4+JRA+ T cells and radiosensitive T8+ T cells are necessary for suppression of primary antigen-specific antibody production in man.

Communicative interactions between subpopulations of human T lymphocytes required for generation of suppressor effector function in a primary antibody response.

J A Distaso

Papers

The isolation and characterization of the human suppressor inducer T cell subset.

Loss of suppressor T cells in active multiple sclerosis. Analysis with monoclonal antibodies.

Relationship between systemic lupus erythematosus T cell subsets, anti-T cell antibodies, and T cell functions.

Communicative interactions between subpopulations of human T lymphocytes required for generation of suppressor effector function in a primary antibody response.

Comparison in T- and B-cell markers in patients with Sjögren's syndrome and systemic lupus erythematosus