The Significance of T-B Collaboration across Haplotype Barriers

Swain, Susan L.; Trefts, Park E.; Tse, Harley Y.; Dutton, Richard

doi:10.1101/sqb.1977.041.01.069

Cited by 32 publications

(33 citation statements)

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“…This is similar to the findings in the murine system that radiation-sensitive, Lytl-2+ T cells can mediate a potent negative allogeneic effect on the capacity of primed cells to develop a secondary in vitro antibody response to antigen (33). In contrast to the findings of others (24,35), who have noted negative, but not positive, allogeneic effects in human antigen-specific antibody production, we have consistently noted potent positive allogeneic effects independent of the presence of antigen in culture, which were only appreciated after the negative allogeneic effects were abrogated either by low-dose irradiation or elimination of OKT8+ T cells. This effect is presumably similar to that seen by the addition of mixed lymphocyte reaction supernatants to unfractionated PBMNC (35,36) or to T cell-depleted populations (36,37).…”

Section: Discussioncontrasting

confidence: 55%

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Lane¹,

Whalen²,

Fauci³

1983

J. Clin. Invest.

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A B S T R A C T We have recently noted marked differences between the in vitro responses of human B lymphocytes to stimulation with soluble antigens vs. stimulation with mitogens. In the present study, these differences were analyzed in terms of the precursor frequencies for the T cells and B cells involved and in terms of the radiation sensitivity of the T cells providing help in the two systems. Marked differences were found between antigen-induced and mitogen-induced systems with regard to T cell precursor frequencies and radiation sensitivity. In contrast, the precursor frequencies for the B cells involved in the two systems were approximately the same. In addition, having developed a system for the study of human antigen-specific B cell responses, we were interested in delineating the nature of the allogeneic effects that might be operative in this system. Marked allogeneic effects, both positive and negative, were noted in this system and will need to be taken into account in any studies that try to address the question of the genetic restriction, if any, that exists in human antigen-specific T cell-B cell collaboration.Appreciation of the marked differences between the antigen-specific and mitogen-induced activation and immunoregulation of human B cell responses will be of importance in understanding the relationship between specificity and nonspecificity of antibody production in normal and disease states. INTRODUCTIONT cell regulation of B cell reactivity is an area of major interest and importance in both animal and human systems. With the recent availability of several systems Address all correspondence to Dr. H. Clifford Lane. Received for publication 20 January 1983 and in revised form 30 March 1983. to study human B cell function in vitro, considerable interest has centered around the precise nature of the T cell regulation of human B cell responses in both polyclonal and antigen-specific assay systems. Unfortunately, there have been conflicting data among sev-. eral of these systems (1-10). Of particular note has been the divergence of results with regard to the radiosensitivity of T cell help and the relative contributions of allogeneic effects in the mitogen-induced vs. antigen-induced human B cell systems. Disagreement with regard to this latter point has led to difficulty in delineating the precise nature of genetic restrictions in T cell-B cell collaboration in antigen-specific responses as well in appreciating the scope of allogeneic effects in co-culture experiments now commonly used in the study of patients with immunemediated or immunodeficiency diseases.Recently, in vitro systems have been developed for the study of antigen-induced, antigen-specific antibody production and secretion into culture supernatants by human B cells (11)(12)(13)(14). The use of enzymelinked immunosorbent assays (ELISA)l has proven to be extremely useful in these studies because of their simplicity, sensitivity, and specificity. These advances have allowed for a more precise study of the mechanisms involved in...

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Section: Discussioncontrasting

confidence: 55%

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Lane¹,

Whalen²,

Fauci³

1983

J. Clin. Invest.

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“…First, the role of histocompatibility or allogeneic differences between the T cells being analyzed and the B cells used as indicator anti-HBs synthesizing lymphocytes could not be assessed (31,32). Selected specific immune responses may be more sensitive to nonspecific allogeneic suppressor T cell activity or be less sensitive to allogeneic helper T cell activity.…”

Section: Co-culture Experimentsmentioning

confidence: 99%

Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers.

Dusheiko¹,

Hoofnagle²,

Cooksley³

et al. 1983

J. Clin. Invest.

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A B S T R A C T It hasIn order to identify the mechanisms for the lack of detectable anti-HBs synthesis by chronic HBsAg carrier lymphocytes, co-culture experiments were performed using T and B lymphocyte fractions that had been purified by affinity chromatography. B lymphocytes from carriers co-cultured with allogeneic irradiated ("helper") T lymphocytes from controls synthesized normal amounts of IgG, IgM, and anti-HBc Dr. Dusheiko was the recipient of a South African Research Council Overseas Scholarship. His present address is

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“…Experiments based on the comparison between allogenic and syngenic immune responses demonstrated strong restriction in some instances (6,8,(10)(11)(12) but weak or absent restriction in others (8,(68)(69)(70)(71)(72). Thus, it is difficult to draw any conclusion on the average level of self restriction from experimental data.…”

Section: Discussionmentioning

confidence: 99%

Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection

Detours

Perelson

1999

Proc. Natl. Acad. Sci. U.S.A.

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Interactions between T cell receptors and peptides bound to molecules encoded by the MHC genes underly T cell activation. More than 1% of T cells are activated by foreign (allogenic) MHC molecules, a phenomenon called alloreactivity. Reconciling the high frequency of alloreactivity with the fact that only 1 T cell in 10 4 -10 6 responds to a given foreign antigen presented on self MHC has been a longstanding puzzle. We show, by using a quantitative model, that this difference follows from the affinity model of T cell selection. Further, we demonstrate that highly alloreactive pre-and post-selection repertoires can be obtained without assuming germline bias of T cell receptors toward recognition of allelespecific MHC residues. It has been proposed that alloreactivity occurs because self and foreign MHCs bind different subsets of self peptides or alter their conformation differently. We find that such effects decrease rather than increase alloreactivity. Overall, our results show that the affinity model of T cell selection can quantitatively explain both self MHC restriction and high alloreactivity.Maturation of T cells in the thymus involves a two-step selection process driven by the affinity of their T cell receptors (TCR) for self peptides presented on proteins encoded by MHC genes. The first step, positive selection (1, 2), disgards thymocytes bearing TCRs with low affinity for MHC-peptide complexes expressed in the thymus. This eliminates T cells that cannot recognize MHC molecules. The second step, negative selection (3, 4), deletes cells with high affinity receptors for thymic MHC-peptide complexes. Thus, removing many self reactive cells. Overall, only 3% of the T cells produced in the thymus have TCRs with the intermediate affinity required to reach the periphery (5).Because MHC genes are extremely polymorphic, two individuals are very unlikely to express the same set of MHC molecules. As a result of positive selection, T cells are self MHC restricted: they recognize pathogens presented by self MHC molecules but ignore them if presented by foreign MHC molecules (6-14). MHC polymorphism is also the main obstacle to tissue transplantation (15). Typically, 1-24% of T cells are alloreactive (16, 17), i.e., they respond to foreign (allogenic) MHC molecules. Reconciling this high alloresponse frequency with the fact that among naive T cells only 1 in 10 4 -10 6 recognizes a given pathogen (18, 19) is a long-standing immunological puzzle. In this paper, we examine quantitatively three hypotheses proposed to explain the high frequency of alloreactivity.The first hypothesis, due to Matzinger and Bevan (20), suggests that the 2-4 orders of magnitude difference between antigen and MHC response frequencies results from the difference in the diversity of these two types of molecule on the surface of antigen presenting cells (APCs). Because each individual expresses only a few distinct MHC molecules and eachThe publication costs of this article were defrayed in part by page charge payment. This article must the...

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The Significance of T-B Collaboration across Haplotype Barriers

Cited by 32 publications

References 0 publications

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Antigen-induced human T cell help. Precursor frequency, radiation sensitivity, and allogeneic effects.

Synthesis of antibodies to hepatitis B virus by cultured lymphocytes from chronic hepatitis B surface antigen carriers.

Explaining high alloreactivity as a quantitative consequence of affinity-driven thymocyte selection

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