CD4+ T cells: specificity and function.
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Biomedical subjects
K Bottomly
Publications and source records attributed to K Bottomly.
Immune recognition and effector function in subsets of CD4 T cells.
T cells expressing the cell surface differentiation antigen CD4 are involved in most immune responses. Our studies address two issues about CD4 T cell responses to antigen: first, how does the T cell receptor come together with its ligand to generate an immune response, and what is the role of the CD4 molecule in this response? Second, are all CD4 T cells identical in their functional activity, and how does the activating signal determine the functional outcome of a response? Our studies outlined below suggest that the T cell receptor and its peptide: class II major histocompatibility complex (MHC) molecule ligand come together in a defined orientation determined in part by the binding of CD4 to both the T cell receptor and its ligand. Our studies suggest that the V beta chain is involved directly in MHC antigen recognition, binding self MHC with low affinity and non-self MHC with high affinity. The selective effect of the Mls locus on V beta expression is believed to reflect the binding of the Mls protein directly to the V beta region. CD4 is described as a co-receptor, forming an inducible part of the T cell receptor and binding to the same class II MHC molecule as that receptor. Studies with both cloned lines and normal CD4 T cell populations suggest the existence of two separable subsets with definable function. One set appears to be specialized for the activation of the humoral immune response, while the other drives the cell-mediated immune responses, particularly those involving the activation of macrophages. These two subsets of CD4 T cells have differential activation requirements, seen particularly in the requirement for interleukin 1 (IL-1) in the activation and clonal expansion of CD4 T cells involved in humoral immunity. This requirement for IL-1 may also be observed in the priming of this subset of CD4 T cells. These studies demonstrate that the optimal activation of CD4+ T cells involves recognition of peptide fragments presented by class II MHC molecules and accessory signals derived from the antigen presenting cells.
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Granulocyte-macrophage colony stimulating factor produced by cloned L3T4a+, class II-restricted T cells induces HT-2 cells to proliferate.
Cloned L3T4a+ antigen-specific, class II-restricted T cells can be subdivided by function and by cytokine production. All cloned T cell lines produce T cell growth factors that can be distinguished by the ability of monoclonal antibodies to inhibit the proliferation of cytokine-dependent T cell lines induced by these T cell growth factors. From these types of analyses, it has been shown that all cloned T cells that help hapten-specific B cells secrete immunoglobulin, produce interleukin 4 (IL 4). Those cloned T cells that fail to help for anti-hapten responses produce neither IL 4 nor interleukin 2 (IL 2), yet release an activity that induces the proliferation of the cytokine-dependent T cell line, HT-2. Additional analysis of the HT-2 stimulating activity has shown that it is indistinguishable from granulocyte macrophage-colony stimulating factor (GM-CSF)--this activity being produced by all cloned T cells tested. Thus GM-CSF is a product of all cloned L3T4a+ T cell lines tested thus far, and can serve as a T cell growth factor for HT-2, as well as a co-factor for in vivo derived T cells.
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Altered splenic T cell function of BALB/cByJ mice infected with mouse hepatitis virus or Sendai virus.
Mouse hepatitis virus and Sendai virus are among the most common viruses naturally infecting laboratory mice. Concanavalin A-stimulated in vitro proliferative responses of splenocytes were examined after infection of BALB/cByJ mice with the JHM strain of mouse hepatitis virus (MHV-JHM) or Sendai virus. Mice were exposed to these viruses by presumed natural routes (per os or intranasally). Immunodepression was marked but transient among BALB/cByJ mice exposed to MHV-JHM. Among mice exposed to Sendai virus and examined over a 21-day period, spleen cells from only one mouse, sacrificed 10 days postinoculation, exhibited a severely impaired ability to respond to concanavalin A. Lymphokine production by spleen cells from control and infected mice was then assessed. IL 2 was either absent or present at very low levels in culture supernates of concanavalin A-unresponsive spleen cells from MHV-JHM-infected mice. Spleen cells from the single Sendai virus-infected mouse also produced very low levels of IL 2. In contrast, IL 1 was detected in supernatants of all spleen cell cultures derived from control, MHV-JHM-infected, or Sendai virus-infected mice. There was not a clear correlation between concanavalin A responsiveness and the ability of spleen cells to produce interferon-gamma. These results stress the importance of using laboratory mice of known microbiological status for immunologic experiments.
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Cloned, Ia-restricted T cells that do not produce interleukin 4(IL 4)/B cell stimulatory factor 1(BSF-1) fail to help antigen-specific B cells.
T cells can be subdivided based on cell surface markers, MHC restriction, function, and production of soluble factors. Analysis of the ability of cloned, Ia-restricted, L3T4+ T cells to induce an in vitro anti-hapten antibody response to hapten-carrier conjugates allowed the definition of three functional subtypes. To examine whether these functional subtypes also differed in the production of soluble mediators, supernatants of the cloned lines were examined for the production of T cell growth factors and factors inducing increased expression of Ia glycoproteins on small resting B cells. All of the cloned lines produced T cell growth factors that could be further differentiated by inhibition with monoclonal antibodies. None of the Ia-restricted, L3T4+ cloned T cell lines that failed to produce IL 4/BSF-1 could provide helper function. Thus, the activation of antigen-specific B cells by helper T cells appears to require IL 4/BSF-1 as a necessary but not sufficient signal for differentiation into antibody-forming cells.
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Direct receptor:receptor interactions between T and B lymphocytes: idiotypic restriction in the antibody response to a cloned helper T cell receptor.
The concept of an immunological network includes the possibility of interactions between receptors on T and B lymphocytes, and such interactions, should they occur, might be expected to influence the repertoire of receptors in each set of cells. Indeed, B cell idiotype specific helper T cells, both MHC-restricted and MHC-unrestricted, have been reported and have been shown to influence the expression of the B cell repertoire. Likewise, it has been reported that B cells may influence the specificity of both regulatory and MHC-restricted T cells. However, interactions between receptors on cloned, MHC-restricted helper T cells and B cells have been difficult to document. Recently, we have taken advantage of an unusual cloned helper T cell line to demonstrate that anti-T cell receptor antibody is produced by direct receptor:receptor interactions between T and B lymphocytes, and that these interactions are not MHC restricted. However, these earlier studies did not address the question of whether such interactions led to activation of B cells expressing multiple distinct antibodies, or whether direct T cell receptor:B cell receptor interactions would lead to an idiotypically restricted B cell response. To address this question, we have now examined both monoclonal and polyclonal responses to the receptor of a conventional, MHC-restricted cloned T cell line, and have shown that these responses are of limited idiotype heterogeneity. Indeed, about 60% of antibodies produced to the receptor of this cloned line share idiotypic determinants, and appear to recognize a single epitope on the receptor. Idiotypically unrelated anti-receptor antibodies, although still specific for the cloned line, recognize what appears to be a distinct epitope on the receptor. These data suggest several conclusions. First, they demonstrate further that direct receptor:receptor interactions between helper T cells and B cells can occur, and can be mutually stimulatory for the two cell types. Second, as shown previously, such interactions are not MHC restricted. Third, such interactions can lead to an idiotypically restricted B cell response. Finally, it is interesting to compared these results with those of other investigators studying idiotype-specific helper T cells. As the cloned line used in this study is a conventional, MHC-restricted, antigen specific helper T cell bearing an alpha:beta heterodimeric receptor complex, and as its interaction with B cells is MHC unrestricted and leads to idiotypically restricted antibody responses, one might propose that such cells are candidates for a clone of an idiotype-specific helper.(ABSTRACT TRUNCATED AT 400 WORDS)
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Cell interactions in the immune system: the role of self recognition in the targeting of nonspecific effector molecules by helper T cells.
Helper T cells are activated by cross-linking of their receptors by antigen:Ia complexes on the surface of antigen-presenting cells and B cells. As a result of this cross-linking, the helper T cell releases several lymphokines that in turn affect the Ia-bearing cell with which the helper T cell is in contact. This interaction is cognate when the effect on the target cell is examined, but it operates by a mechanism that is neither antigen specific nor MHC restricted. Whether the cognate nature of this interaction reflects solely the intimate contact of the T cell with the Ia antigen-bearing cell or whether it reflects a receptor-directed focal release of lymphokines remains to be determined. The molecular basis for functional diversity in helper T cells will have to be determined by examining the factors that regulate lymphokine gene expression in such cells, a process that appears to act at several levels.
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A cloned T cell line that selectively augments antibody responses of phosphorylcholine-specific B cells bearing the T15 idiotype.
Helper T (Th) cells have shown to be heterogeneous both in their function and in their specificity. Several studies have demonstrated that there exist Th cells which do not appear to be specific for antigen:Ia complexes (not H-2 restricted) but interact with the target B cell via recognition of immunoglobulin idiotypic determinants. In analyzing anti-phosphorylcholine (PC) responses, such idiotype-specific Th cells are characterized by 1) their ability to increase responses to phosphorylcholine by augmenting selectively the activation of T15-idiotype-bearing PC-specific B cells, 2) their ability to bind specifically to T15-bearing immunoglobulin and 3) the dependence of their maturation on circulating T15 idiotype rather than Ia. Our aim is to explore further the relationship between Ia-specific and T15-specific Th cells. These studies describe the first step in comparing specificity and function of idiotype-specific Th cells to other known Th cells by the cloning of a T15-specific Lyl T cell (ThId) with properties consistent with those described for uncloned populations. The cloned ThId cells generated do not activate B cells to secrete antibody but augment anti-PC plaque forming cell (PFC) responses induced by Ia-restricted Th cells. This augmentation is seen only in the T15-bearing PFC responses even though non-T15-bearing B cells are equally accessible, and it is seen only in PC responses and not responses to TNP under identical culture conditions.(ABSTRACT TRUNCATED AT 250 WORDS)
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Distinct functional phenotypes of cloned Ia-restricted helper T cells.
Analysis of activation of phosphorylcholine (PC)-specific B cells by a large number of different cloned, self Ia-specific helper T cell (Th) clones has permitted the classification of such T cells into four distinct functional types. Types 1 and 2 induce B cells to secrete anti-PC antibody in an antigen-specific, Ia-restricted fashion. Type 3 cells induce antigen-specific, Ia-restricted B cell proliferation, but do not lead to specific antibody formation, and have been shown previously to have suppressor functions. Type 4 cells are autoreactive, and induce antigen-independent B cell activation and antibody secretion. The distinction between type 1 and type 2 Th clones was analyzed in detail. In bulk cultures, type 1 cloned lines generate an idiotypically heterogeneous anti-PC antibody response, whereas type 2 cloned lines induce a larger response that is dominated by the T15 idiotype. In limiting-dilution analyses, type 2 cells induce fourfold more T15+, PC-specific precursor B cells than do type 1 cells, and in addition, induce larger burst sizes for T15+, PC-specific B cells. Type 4 clones can also be subdivided into cells that are type 1-like, and cells that are type 2-like. These differences in functional phenotype are seen over a broad range of antigen and cell doses. Detailed analysis of the behavior of these distinct functional types of Th should allow a better understanding of the functional properties of mixed populations of antigen-primed, Ia-restricted Th cells.
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T15-specific helper T cells: analysis of idiotype specificity by competitive inhibition analysis.
Optimal activation of T15 idiotype-bearing B cells has been shown previously to be influenced by two subsets of Thy-1+, Ly-1+,2-sIg- helper T cells. One of the helper T cell sets appears to be T15 specific in that its presence results in a selective augmentation of T15-bearing anti-phosphorylcholine (PC) plaque-forming cell responses. To determine the precise specificity of the idiotype-specific helper T cell (ThId), Ly-1 T cells were tested in an in vitro anti-PC response for their ability to bind directly to T15 myeloma protein-coated plastic plates. Specificity of this binding was ascertained by competitive inhibition of plate binding using idiotypically related myeloma or hybridoma proteins. These data suggest that the Ly-1 T cells which augment T15-bearing plaque-forming cell responses can bind to T15-coated plates and are T15 idiotype specific. This approach is being used currently to attempt to clone ThId cells to further analyze their activation requirements and specificities.
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Modes of cell:cell communication in the immune system.
Different cell types in the immune system appear to mediate their effects by markedly different means. B lymphocytes couple information for specificity with information for function in a single long-range molecule, antibody. Major histocompatibility complex (MHC)-restricted T cells, which we have analyzed in detail, appear to recognize antigen only on the surface of cells bearing the appropriate MHC gene product. This interaction provokes the T cell to release short-range, non-antigen-specific mediators (lymphokines) that preferentially act on the target cell bearing the antigen and stimulating the T cell. Regulatory T cells appear to make antigen-specific long-range molecules that, like antibody, combine specificity with information for function. However, unlike antibody molecules, these regulatory T cell products display recognition for particular target cells in the form of genetic restrictions. These behaviors are compared to strategies of cell:cell communication in the nervous system.
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The role of immunoglobulin and B cells in T cell ontogeny and repertoire formation--a commentary.
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1984: all idiotypes are equal, but some are more equal than others.
Our analysis of idiotypic dominance suggests that 3 elements play an important role. The first is the genetic material that encodes the dominant idiotype. As dominant idiotypes appear to reflect germ-line-encoded sequences, one can not express a particular idiotype unless that sequence is present in the germ line. The germ-line-encoded sequences, in turn, would, I predict, be specific for commonly encountered or former environmental pathogens. The second element is the environmental antigens themselves. These antigens will induce the production of idiotype, and will prime idiotype-bearing B cells, such that idiotypic dominance emerges. In the absence of such influences, the pattern of idiotypic expression appears to differ. The third influence is regulatory. My own studies have shown that idiotype found in normal serum plays an important role in the maturation and/or function of one such cell, an idiotype-specific helper T cell. It is my working hypothesis that such cells play several roles in idiotypic dominance, but that this is the least of their important roles. Rather, such cells, being specific for idiotopes associated with antibodies specific for environmentally encountered pathogens, would be important in the priming and rapid reactivation of B cells bearing such idiotopes. As such, they speak to the basic role of the immune system, the protection of the organism from infection.
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Subpopulations of B cells distinguished by cell surface expression of Ia antigens. Correlation of Ia and idiotype during activation by cloned Ia-restricted T cells.
We have investigated in vitro the induction of antibody responses to phosphorylcholine (PC) by cloned T helper (Th) cell lines. The cloned Th cells are antigen specific, in this case ovalbumin (OVA), self-Ia recognizing, and induce antibody secretion only if the hapten, PC, is physically linked to the carrier (OVA) molecule. The plaque-forming cell (PFC) response generated in the presence of cloned Th cells is idiotypically diverse with 5-40% of the secreting B cells bearing the TEPC-15 (T15) idiotype. The interaction of the cloned Th cells and unprimed B cells requires recognition of B cell surface Ia glycoproteins for all B cells activated to secrete anti-PC antibody, whether they be T15-bearing or not. More importantly, however, effective interaction between a cloned Th cell and a B cell is determined by the quantity of B cell surface Ia glycoproteins. Our results indicate that quantitative differences in B cell surface Ia antigens are directly related to B cell activation by the cloned Th cell. The high Ia density B cells are most easily activated by cloned Th cells, and these appear to be mainly non-T15-bearing. These data suggest that the failure of cloned Th cells to effectively activate T15-bearing B cells in vitro may be due to the lower relative Ia density of these B cells and therefore to their inability to interact effectively with cloned Ia-recognizing Th cells. These results imply that monoclonal T cells may distinguish between T15-bearing and non-T15-bearing B cells based on their Ia density.
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The role of B-cell I region encoded antigens in T-cell dependent B-cell activation: I region encoded antigen density correlates with idiotype expression.
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A cloned, antigen-specific, Ia-restricted Lyt-1+,2- T cell with suppressive activity.
The correlation between cell surface antigen phenotype and function is one of the cornerstones of modern cellular and clinical immunology. It is based on the collective experience of many investigators examining populations of T cells. The availability of cloned lines of T cells now allows us to ask whether all cells sharing cell surface antigen phenotype are functionally equivalent. We have examined a large number of antigen-specific, self-Ia recognizing, cloned Lyt-1+,2- T cell lines for their ability to help B cells proliferate and secrete antibody in response to antigen. All of these lines induced antigen-specific, Ia-restricted B cell proliferation. One line did not induce antibody secretion. This line, indeed suppressed the plaque-forming cell response of B cells helped by any of the other cloned T cell lines tested. Suppression in this system had all the characteristics of classical T cell help, apart from the ultimate outcome. That is, the suppressor cell acted upon the B cell in a manner that was antigen-specific, Ia-restricted, and required hapten-carrier linkage. We interpret our results as supporting the basic paradigm of an association of cell surface antigen phenotype with function, with an important proviso. Not all Ly1, Ia-restricted T cells may be capable of helper function, and some in fact may be suppressive. Experimental conditions favoring the generation of such cells, or disease states in which such cells reside within the Ly1 or T4+ subset, may give rise to disparities between phenotype and function similar to that observed here at the clonal level.(ABSTRACT TRUNCATED AT 250 WORDS)
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Helper T cells specific for protein antigens: role of self major histocompatibility complex and immunoglobulin gene products.
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Antigen-specific helper T cells required for dominant idiotype expression are not H-2 restricted.
Two synergizing antigen-specific helper T (Th) cell populations are required for an optimal TEPC15 (T15)-dominated antiphosphorylcholine (PC) plaque- forming cell response . In these studies, the two Th cell sets are shown to differ in their requirements for recognition of self-major histocompatibility complex (MHC)-encoded determinants by testing the ability of Th cells from F(1) {arrow} parent bone marrow chimeras to collaborate with PC-specific B cells bearing MHC-encoded determinants of either parental haplotypes. Previous studies have shown that one antigen-specific Th cell population is required for T-dependent anti-PC responses and activates PC-specific B cells only if the hapten, PC, is physically linked to the priming antigen. This Th cell, referred to as ThMHC, induces anti-PC responses that are mainly non-T15 in character, and it appears to be identical to the conventional antigen- specific Th cell. In these experiments, using T cells from (A X B)F(1) {arrow} parent A chimeras, ThMHC cells requiring hapten-carrier association provide help for F(1) and parent A B cells but not for B cells from parent B, thus confirming that the activity of the conventional Th cell is H-2 restricted . The second antigen-specific Th cell population, whose function is measured in the presence of the ThMHC cell set, preferentially activates T15-bearing B cells. This Th cell set (ThId) is missing in mice expressing low levels of T15-bearing antibody and can be restored by the addition of antigen-specific T cells from donors expressing high levels of circulating T15 Id. These studies demonstrate that T cells from F(1) {arrow} parent chimeras that express substantial levels of T15-bearing anti-PC antibody could provide ThId cell activity for the selective activation of T15-bearing B cells of F(1) and both parental H-2 types. These results imply that whereas the activity of conventional, ThMHC, cells is clearly H-2 restricted, ThId cells from the same chimeric donors are not required to recognize antigen in association with self-MHC-encoded determinants for successful T-B collaboration .
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