Rapid changes in specificity within single clones of cytolytic effector cells

Reimann, Jörg; Miller, Richard G.

doi:10.1016/0092-8674(85)90205-3

Cited by 26 publications

(10 citation statements)

References 66 publications

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“…The process of somatic diversification continues after B cell ontogeny in the course of a humoral immune response to antigen in vivo ; the data on somatic diversification of the TCR phenotype during antigen-driven T cell development are preliminary [18,[31][32][33][34]. The nature of the T cell-mediated alloresponse is uncertain: it might be a primary response, or it might reflect cross-reactive specificity patterns present in the antigen-primed self-restricted T cell pool [35,361.…”

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confidence: 99%

Use of Vpß.8 genes in splenic Lyt‐2⁺ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Reimann

Bellan

1986

Eur J Immunol

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The cytotoxic response of cell sorter-purified small Lyt-2+ splenic cytotoxic lymphocyte precursors from 10 individual C57BL/6 mice to mutant class I H-2Kbm1 or H-2Dbm14 allodeterminants was analyzed under limiting dilution conditions. The cytotoxic activity of anti-bm1-specific or anti-bm14-specific cytotoxic T lymphocyte (CTL) populations (selected for a high probability of clonality) was tested against F23 hybridoma cells; F23+ CTL clones lysed F23 hybridoma targets but F23- CTL clones did not. In the C57BL/6 anti-bm1 mixed lymphocyte reaction, 36% (range 29-48%) of the generated CTL clones were F23+; in the B6-anti-bm14 mixed lymphocyte reaction, 45% (range 34-49%) of the generated CTL clones were F23+. Hence, a large fraction of the anti-bm1- or anti-bm14-reactive CTL clones from C57BL/6 mice use V beta.8 genes to construct these allospecific T cell receptor phenotypes, but no extensive variation in the use of V beta.8 genes in the construction of allospecific T cell receptor phenotypes of restricted heterogeneity is found in individual mice of the same strain.

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confidence: 99%

Use of Vpß.8 genes in splenic Lyt‐2⁺ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Reimann

Bellan

1986

Eur J Immunol

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“…These findings might explain data such as reported by Reimann et al [2,31 concerning specificity changes in individual LD cultures upon repeated restimulations without having to assume structural variations of their receptors. Our observations also suggest caution when performing T cell repertoire studies by LD methods.…”

Section: Discussionmentioning

confidence: 49%

Growth‐dependent variation of major histocompatibility complex (MHC) restriction and expression of Ly‐2 and CD3/α/βT cell receptor in cloned cytotoxic T cells

et al. 1988

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The specificity of major histocompatibility complex (MHC)-restricted antigen recognition by cytotoxic T cells (CTL) has been clearly correlated to the alpha/beta T cell receptor (TcR) complex on the T cell surface. Occasional changes in the specificity of in vitro cultivated CTL clones, therefore, have been suspected to result from alterations of the genes coding for the TcR alpha and/or beta chain. Here we demonstrate that pronounced variations in the stringency of MHC restriction, previously reported to occur during long-term culture of 2,4,6-trinitrophenyl (TNP)-specific CTL clones, may occur rapidly in a growth-dependent, reversible manner, i.e. without structural TcR variation. Several H-2b TNP-specific CTL clones were shown to possess strong cross-reactivity for H-2k TNP target cells when seeded at low cell numbers, but exhibit reduced or undetectable cross-reaction to H-2k TNP in high-density cultures. Another clone revealed "heteroclitic" properties with significantly stronger cytotoxic activity towards allogeneic (H-2k) than syngeneic (H-2b) TNP-modified target cells. In this case dilute cultures appeared as exclusively allo-MHC restricted, whereas dense cultures were allo/self cross-restricted. In all instances these phenomena were accompanied by cell density-dependent quantitative changes in the expression of Ly-2 and T cell antigen receptor. CTL from dilute cultures had at least 2-fold higher surface concentrations of Ly-2 and CD3 antigens than cells from dense cultures while other surface markers such as Thy-1 or LFA-1 were completely identical. No such effects were observed for CTL clones exhibiting cell density-independent specificity patterns. We conclude from these findings that (a) the stringency of MHC restriction specificity may be significantly affected by the amount of expressed TcR and/or Ly-2 molecules, (b) CTL possess mechanisms to regulate Ly-2 and TcR expression and, hence, their MHC-restricted antigen recognition, and (c) the ability to regulate Ly-2 and TcR expression may be altered during prolonged culture of a CTL clone.

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“…More explicitely , such specificity changes were demonstrated in a subsequent study [19], proving altered specificity of individual limiting dilution cultures upon repeated cytotoxicity assays.…”

Section: Discussionmentioning

confidence: 92%

Hapten‐specific cytotoxic T cell clones undergo somatic variation of their antigen recognition specificity

et al. 1986

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Two experimental systems have demonstrated somatic variation of antigen recognition specificity of long-term cytotoxic T cell (CTL) clones. System 1 used CTL clone BT7.4.1 with strict specificity for Kb/TNP, which had been continuously cultured for 15 months in the presence of H-2b/TNP stimulator cells and interleukin 2. Upon removal of the TNP antigen from the cultures, 99% of the clone cells within about 10 cell divisions lost their ability to grow in the presence of antigen and interleukin 2 (lethal variants). Of the surviving 1%, about 60% retained the ability to lyse target cells in the presence of lectins but only 12% could be considered as "wild type" BT7.4.1 cells, i.e. they still specifically lysed H-2b/TNP-bearing target cells. The majority of the growing cells, thus, had to be considered as specificity loss variants. Several specificity loss variants were established in culture and were shown to express membrane-bound T cell "receptor" heterodimer similar to their TNP-specific ancestor, BT7.4.1. Principally the same types of variants were generated in cultures growing in the presence of TNP antigen, although in quantitatively reduced numbers. Under these conditions the specific stimulator cells appeared to impose a significant selective advantage for "wild type" CTL since even after 15 months the cultures fully retained their specificity for the nominal antigen. In system 2, the development of cytolytic fine specificity of a panel of 42 individual Kb/TNP-specific CTL clones was followed over a period of 8 months of in vitro culture. At the beginning of the test, 37 of these clones exhibited significant cross-reactivity for lysis of H-2k/TNP target cells. This number of cross-reactive clones continuously diminished with time and dropped to only 4 clones after 8 months in culture. All 42 clones retained their original Kb/TNP specificity and after losing their reactivity for H-2k/TNP usually showed no decrease but rather an increase in their cytotoxic activity towards Kb/TNP target cells. Loss of H-2k/TNP cross-reactivity was not accompanied by loss of Lyt-2 or of LFA-1 surface antigens or by loss of sensitivity of the cytotoxicity to inhibition by anti-Lyt-2 or by anti-LFA-1 antibody. We conclude from these observations that in vitro cultivated CTL clones, at least those of C57BL/6 anti-TNP-C57BL/6 specificity, are not stable in terms of their antigen recognition specificity.(ABSTRACT TRUNCATED AT 400 WORDS)

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Rapid changes in specificity within single clones of cytolytic effector cells

Cited by 26 publications

References 66 publications

Use of Vpß.8 genes in splenic Lyt‐2⁺ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Use of Vpß.8 genes in splenic Lyt‐2⁺ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Growth‐dependent variation of major histocompatibility complex (MHC) restriction and expression of Ly‐2 and CD3/α/βT cell receptor in cloned cytotoxic T cells

Hapten‐specific cytotoxic T cell clones undergo somatic variation of their antigen recognition specificity

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Rapid changes in specificity within single clones of cytolytic effector cells

Cited by 26 publications

References 66 publications

Use of Vpß.8 genes in splenic Lyt‐2+ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Use of Vpß.8 genes in splenic Lyt‐2+ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Growth‐dependent variation of major histocompatibility complex (MHC) restriction and expression of Ly‐2 and CD3/α/βT cell receptor in cloned cytotoxic T cells

Hapten‐specific cytotoxic T cell clones undergo somatic variation of their antigen recognition specificity

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Use of Vpß.8 genes in splenic Lyt‐2⁺ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice

Use of Vpß.8 genes in splenic Lyt‐2⁺ cytotoxic lymphocyte precursors reactive to bm1 or bm14 alloantigen in individual C57BL/6 mice