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. 2004 Mar 16;101(11):3874-9.
doi: 10.1073/pnas.0400606101. Epub 2004 Mar 4.

Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire

Booki Min  1 , Gilles Foucras, Martin Meier-Schellersheim, William E Paul
Affiliations

Spontaneous proliferation, a response of naive CD4 T cells determined by the diversity of the memory cell repertoire

Booki Min et al. Proc Natl Acad Sci U S A. .

Abstract

T cell numbers are maintained within narrow ranges in vivo. Introduction of naïve cells into lymphopenic environments results in proliferation and differentiation driven by the recognition of peptide/MHC complexes and by cytokine signaling. This process, often described as homeostatic proliferation, is here referred to as spontaneous proliferation. We show that, although the presence of memory CD4 T cells of broad repertoire efficiently inhibits proliferation/differentiation of naïve CD4 T cells, a memory population of similar size comprised of cells with a repertoire of limited diversity fails to do so, implying that cells of a given specificity prevent responses of cells of the same or related specificity. This finding suggests that the immune system has evolved mechanisms to attain a memory cell repertoire of great diversity independently of foreign antigens.

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Figures

Fig. 1.
Fig. 1.
CD4 T cells of single specificity fail to block the proliferation of polyclonal naïve CD4 T cells. (A) A total of 2 × 106 CFSE-labeled naïve CD4 T cells from Ly5.1 B10.A, BALB/c, and C57BL/10 mice were transferred into 5C.C7 Tg Rag2-/-, DO.11 Tg Rag2-/-, and AND Tg Rag2-/- or Marilyn Tg Rag2-/- mice, respectively. Shown is CFSE profile of transferred cells (gated on Ly5.1+, KJ1.26+, Vβ3-, and Vβ6- CD4+, respectively) at 7 days after transfer. (B) CFSE-labeled naïve Ly5.1 CD4 and CD8 T cells were transferred into OT-I Tg Rag1-/- mice. CFSE profile was measured at 7 days after transfer (gated on Ly5.1+ CD4+). (C) 5C.C7 Tg Rag2-/- mice received 2 × 106 CFSE-labeled Ly5.1 CD4 T cells and were simultaneously implanted with a miniosmotic pump containing 0, 0.01, or 1 mg of cytochrome C protein. Lymph node CD4 T cells were analyzed for CD44 expression after 7 days of transfer. (D) Ly5.1 naïve CD4 T cells were transferred into 5C.C7 Tg Rag2-/- mice that had been immunized 60 days earlier by implantation of a miniosmotic pump containing 1 mg of cytochrome C protein. CD44 expression was measured 7 days after transfer. The bold line represents Ly5.1 cells and the filled area represents endogenous Tg cells. Experiments were repeated more than twice with similar results.
Fig. 2.
Fig. 2.
Polyclonal CD4 T cells that had undergone proliferation in lymphopenic mice are able to regulate the proliferation of newly transferred CD4 T cells. (A) B10.A Rag2-/- mice received 2 × 106 CFSE-labeled Ly5.1 naïve CD4 T cells. (B) B10.A Rag2-/- mice that had received 2 million Ly5.2 CD4 T cells 60 days before were given 2 × 106 CFSE-labeled naïve Ly5.1 CD4 T cells. Lymph nodes were taken 7 days after the second transfer, and CFSE profile and BrdUrd uptake of Ly5.1 CD4 T cells were measured. Similar results were observed when 5C.C7 Tg Rag2-/- mice were used as recipients (data not shown). Similar results were obtained from three independent experiments.
Fig. 3.
Fig. 3.
Repertoire diversity, but not cell number, depends on the number of transferred cells. (A) Different numbers (104 to 107) of Ly5.2 CD4 T cells were transferred into Rag2-/- mice. Total lymph node CD44bright CD4 T cell numbers from each recipient were calculated by FACS analysis 60 days after transfer. Shown is one representative (two to three mice) from three independent experiments. (B) CD44bright CD4 T cells were sorted from individual Rag2-/- recipients that had received different numbers of CD4 T cells 2 months earlier. Repertoires of selected Vβs of CD44bright CD4 T cells were analyzed by immunoscope technique. (C) Statistical analysis of repertoire incompleteness. Each point represents an individual mouse.
Fig. 4.
Fig. 4.
Repertoire diversity of preexisting CD44bright CD4 T cells determines the behavior of newly transferred cells. (A and B) Rag2-/- recipients as described in Fig. 3A received 2 × 106 CFSE-labeled Ly5.1 naïve CD4 T cells. Seven days after transfer, total numbers of CD44bright Ly5.1 CD4 T cells and CFSE profiles from lymph nodes and liver were determined. The proportion of cells that had undergone more than seven divisions is indicated. Similar results were obtained when 5C.C7 Tg Rag2-/- mice were used as recipients (data not shown). (C) Proliferation rates of both Ly5.1 and Ly5.2 CD44bright T cells were also measured after an in vivo BrdUrd injection. Groups consisted of four to six individual mice from two independent experiments. (D) Rag2-/- mice received 0.1 × 106 Ly5.2 CD4 T cells. Fifty days later, these mice received 2 × 106 CD44dull Ly5.1 CD4 T cells. Ly5.2 and Ly5.1 CD44bright CD4 T cells were sorted from individual mice at 7 days after Ly5.1 cell transfer. Shown are immunoscope profiles of a set of Vβs from Ly5.1 (red) and Ly5.2 (blue) cells from two individual mice.
Fig. 5.
Fig. 5.
CD25+ regulatory T cells are not responsible for the homeostatic regulation. FACS-sorted Ly5.1 CD25+ CD4 T cells and Ly5.2 CD25- CD4 T cells were mixed at a 1:9 ratio, and different numbers (3 × 104 to 3 × 106) were transferred into Rag2-/- mice. One month after transfer, the proportion and total number of Ly5.1 CD4 T cells were calculated from seven to eight individual mice per each group.
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References

    1. Freitas, A. A. & Rocha, B. (2000) Annu. Rev. Immunol. 18, 83-111. - PubMed
    1. Jameson, S. C. (2002) Nat. Rev. Immunol. 2, 547-556. - PubMed
    1. Ernst, B., Lee, D.-S., Chang, J. M., Sprent, J. & Surh, C. D. (1999) Immunity 11, 173-181. - PubMed
    1. Bender, J., Mitchell, T., Kappler, J. & Marrack, P. (1999) J. Exp. Med. 190, 367-373. - PMC - PubMed
    1. Gudmundsdottir, H. & Turka, L. A. (2001) J. Immunol. 167, 3699-3707. - PubMed

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