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.

In an attempt to account for antibody specificity and complementarity in terms of structure, human kappa-, human lambda-, and mouse kappa-Bence Jones proteins and light chains are considered as a single population and the variable and constant regions are compared using the sequence data available. Statistical criteria are used in evaluating each position in the sequence as to whether it is essentially invariant or group-specific, subgroup-specific, species-specific, etc. Examination of the invariant residues of the variable and constant regions confirms the existence of a large number of invariant glycines, no invariant valine, lysine, and histidine, and only one invariant leucine and alanine in the variable region, as compared with the absence of invariant glycines and presence of three each of invariant alanine, leucine, and valine and two each of invariant lysine and histidine in the constant region. The unique role of glycine in the variable region is emphasized. Hydrophobicity of the invariant residues of the two regions is also evaluated. A parameter termed variability is defined and plotted against the position for the 107 residues of the variable region. Three stretches of unusually high variability are noted at residues 24-34, 50-56, and 89-97; variations in length have been found in the first and third of these. It is hypothesized that positions 24-34 and 89-97 contain the complementarity-determining residues of the light chain-those which make contact with the antigenic determinant. The heavy chain also has been reported to have a similar region of very high variability which would also participate in forming the antibody-combining site. It is postulated that the information for site complementarity is contained in some extrachromosomal DNA such as an episome and is incorporated by insertion into the DNA of the structural genes for the variable region of short linear sequences of nucleotides. The advantages and disadvantages of this hypothesis are discussed.

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An analysis of the sequences of the variable regions of bence jones proteins and myeloma light chains and their implications for antibody complementarity

This essay summarizes my 40 years of research in immunology. As a young physician, I encountered a patient with Waldenstrom's macroglobulinemia, and this inspired me to study the structure of IgM. I began to ask how antibody responses are regulated. In the late 1960s, the essential role of T cells in antibody production had been reported. In search of molecules mediating T cell helper function, I discovered activities in the culture supernatant of T cells that induced proliferation and differentiation of B cells. This led to my life's work: studying one of those factors, interleukin-6 (IL-6). To my surprise, IL-6 turned out to play additional roles, including myeloma growth factor and hepatocyte-stimulating factor activities. More importantly, it was involved in a number of diseases, such as rheumatoid arthritis and Castleman's disease. I feel exceptionally fortunate that my work not only revealed the framework of cytokine signaling, including identification of the IL-6 receptor, gp130, NF-IL6, STAT3, and SOCS-1, but also led to the development of a new therapy for chronic inflammatory diseases.

Interleukin-6: from basic science to medicine--40 years in immunology.

In this Timeline, we describe the characteristics of tumour antigens that are recognized by spontaneous T cell responses in cancer patients and the paths that led to their identification. We explain on what genetic basis most, but not all, of these antigens are tumour specific: that is, present on tumour cells but not on normal cells. We also discuss how strategies that target these tumour-specific antigens can lead either to tumour-specific or to crossreactive T cell responses, which is an issue that has important safety implications in immunotherapy. These safety issues are even more of a concern for strategies targeting antigens that are not known to induce spontaneous T cell responses in patients.

Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy.

Although T cell help for B cells was described several decades ago, it was the identification of CXCR5 expression by B follicular helper T (Tfh) cells and the subsequent discovery of their dependence on BCL6 that led to the recognition of Tfh cells as an independent helper subset and accelerated the pace of discovery. More than 20 transcription factors, together with RNA-binding proteins and microRNAs, control the expression of chemotactic receptors and molecules important for the function and homeostasis of Tfh cells. Tfh cells prime B cells to initiate extrafollicular and germinal center antibody responses and are crucial for affinity maturation and maintenance of humoral memory. In addition to the roles that Tfh cells have in antimicrobial defense, in cancer, and as HIV reservoirs, regulation of these cells is critical to prevent autoimmunity. The realization that follicular T cells are heterogeneous, comprising helper and regulatory subsets, has raised questions regarding a possible division of labor in germinal center B cell selection and elimination.

Follicular Helper T Cells

SummarySuspensions containing normal thymus, spleen, or marrow cells were injected into irradiated syngeneic mice which were subsequently given antigen. Normal spleen cells produced discrete areas ...

Thymus-Marrow Cell Combinations. Synergism in Antibody Production.∗:

The data confirm the hypothesis of interaction between thymus and marrow cells, although the nature of this interaction is obscure.

Immunocompetence of Transferred Thymus-Marrow Cell Combinations

SummaryThe enhanced immunocompetence of transferred thymus-marrow cell combinations was demonstrated using the Jerne plaque-assay method. Suspensions containing both thymus and marrow cells produced more antibody to sheep erythrocytes when transferred to irradiated syngeneic hosts and stimulated with antigen than could be accounted for by the summation of thymus- or marrow-cell activities considered singly. Living homologous thymus cells were required, since the following materials were incapable of interacting with isologous marrow cells; sonicated or irradiated (53Or) mouse thymus cells or living rat thymus cells. The thymus of the host was not necessary for demonstrating thymus-marrow immunocompetence.

Thymus-marrow immunocompetence iii. The requirement for living thymus cells.

The growth and function of bone marrow, thymus, and spleen cell suspensions were studied after injection into irradiated recipients. Parental and F1 hybrid mice (C57L, A/He, and C57L X A/He) were used as both donors and recipients. Marrow cell function was shown by enlargement of the recipient spleen. Thymus cell function was indicated by the enhanced antibody production to sheep RBC by combinations of thymus and marrow cells. Spleen cell function was shown by production of antibodies to sheep RBC. Both marrow and spleen cells showed “hybrid resistance,” i.e., they functioned better when donor and recipient were syngeneic (either parent ➞ parent, or F1 ➞ F1) than when they were allogeneic (parent ➞ F1, or F1 ➞ parent). Similarly, C57BL thymus cells functioned well in C57L but not in LAF1 hybrid recipient strains. Thymus cells, on the contrary, functioned as well in LAF1 as in A recipients. Growth of F1 marrow was inhibited by parental thymus cells only in syngeneic parental recipients and not in F1 recipients. This may represent the immunological reequipment of irradiated parental hosts by parental thymus cells. Hybrid resistance was not seen if parental spleen cells were enclosed with antigen in Millipore diffusion chambers and placed in FF1 recipients. This suggests that hybrid resistance depends upon contact between parental and F1 cells

E A Chaperon

Papers

Thymus-Marrow Cell Combinations. Synergism in Antibody Production.∗:

Immunocompetence of Transferred Thymus-Marrow Cell Combinations

Thymus-marrow immunocompetence iii. The requirement for living thymus cells.

Thymus-marrow immunocompetence. IV. The growth and immunocompetence of transferred marrow, thymus, and spleen cells in parent and F1 hybrid mice.

Immunocompetence of transferred thymus-marrow cell combinations. J Immunol 97;6:828-32, 1966.