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. 1999 Oct 18;190(8):1059-68.
doi: 10.1084/jem.190.8.1059.

PIM1 reconstitutes thymus cellularity in interleukin 7- and common gamma chain-mutant mice and permits thymocyte maturation in Rag- but not CD3gamma-deficient mice

H Jacobs  1 , P Krimpenfort, M Haks, J Allen, B Blom, C Démollière, A Kruisbeek, H Spits, A Berns
Affiliations

PIM1 reconstitutes thymus cellularity in interleukin 7- and common gamma chain-mutant mice and permits thymocyte maturation in Rag- but not CD3gamma-deficient mice

H Jacobs et al. J Exp Med. .

Abstract

The majority of lymphomas induced in Rag-deficient mice by Moloney murine leukemia virus (MoMuLV) infection express the CD4 and/or CD8 markers, indicating that proviral insertions cause activation of genes affecting the development from CD4(-)8(-) pro-T cells into CD4(+)8(+) pre-T cells. Similar to MoMuLV wild-type tumors, 50% of CD4(+)8(+) Rag-deficient tumors carry a provirus near the Pim1 protooncogene. To study the function of PIM proteins in T cell development in a more controlled setting, a Pim1 transgene was crossed into mice deficient in either cytokine or T cell receptor (TCR) signal transduction pathways. Pim1 reconstitutes thymic cellularity in interleukin (IL)-7- and common gamma chain-deficient mice. In Pim1-transgenic Rag-deficient mice but notably not in CD3gamma-deficient mice, we observed slow expansion of the CD4(+)8(+) thymic compartment to almost normal size. Based on these results, we propose that PIM1 functions as an efficient effector of the IL-7 pathway, thereby enabling Rag-deficient pro-T cells to bypass the pre-TCR-controlled checkpoint in T cell development.

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Figures

Figure 1
Figure 1
Incidence of T cell lymphomas in MoMuLV-infected Rag2-deficient mice. MoMuLV-infected Rag2-deficient newborn mice develop T cell lymphomas at a very high incidence, with an average latency period of 150 d. Within 200 d, 81% (150/185) of the mice had developed lymphomas. The tumor incidence and LD50 (150 d) of MoMuLV-infected Rag-mutant mice are comparable to those observed previously in MoMuLV-infected wild-type mice 35.
Figure 2
Figure 2
Most T cell tumors in MoMuLV-infected Rag2-deficient mice bypass the Rag2-mediated differentiation arrest. Typical examples of FACS™ analysis of MoMuLV-induced T cell lymphomas in Rag2-deficient mice are shown. In Rag-deficient mice, differentiation of thymocytes is arrested at the CD4−8−24+25+44low DN stage of α/β T cell development. Whereas tumors 125 and 126 are representative examples for DN tumors, most lymphomas bypass this differentiation arrest and develop into DP or combined DN/DP immature T cell lymphomas. For example, tumor 49 represents a “transitional tumor” from the ISP to DP stage, tumor 108 is a DN/DP tumor, tumors 103 and 118 are DP, and tumors 130 and 136 are “differentiating tumors” from DN to ISP to DP. The tumors with a mixed phenotype, like 49, 130, and 136, are clonal, as the genomes of sorted fractions carry identical proviral insertions (data not shown).
Figure 2
Figure 2
Most T cell tumors in MoMuLV-infected Rag2-deficient mice bypass the Rag2-mediated differentiation arrest. Typical examples of FACS™ analysis of MoMuLV-induced T cell lymphomas in Rag2-deficient mice are shown. In Rag-deficient mice, differentiation of thymocytes is arrested at the CD4−8−24+25+44low DN stage of α/β T cell development. Whereas tumors 125 and 126 are representative examples for DN tumors, most lymphomas bypass this differentiation arrest and develop into DP or combined DN/DP immature T cell lymphomas. For example, tumor 49 represents a “transitional tumor” from the ISP to DP stage, tumor 108 is a DN/DP tumor, tumors 103 and 118 are DP, and tumors 130 and 136 are “differentiating tumors” from DN to ISP to DP. The tumors with a mixed phenotype, like 49, 130, and 136, are clonal, as the genomes of sorted fractions carry identical proviral insertions (data not shown).
Figure 3
Figure 3
Tumor differentiation of MoMuLV-induced Rag-deficient tumors correlates with proviral insertion into the Pim1 locus. 76 selected tumors were classified according to the expression of CD4 and CD8 markers into CD4−8− (DN), CD4−8+24+ or CD4+8−24+ immature single positive (ISP), and CD4+8+ (DP) tumors, as well as tumors with a mixed phenotype, being either ISP and (+) DP or DN and (+) DP. Proviral insertions into the Pim1 and Pim2 loci of these tumors are given as percentages. 27% (15/56) of the tumors that expressed CD4 and/or CD8 (i.e., differentiated tumors) harbor a proviral insertion near Pim1, as compared with only 10% (2/20) in DN (undifferentiated) tumors. In the DP tumors, 50% (9/18) carry an insertion near Pim1. No proviral integrations in the Pim2 locus were found in the 76 tumors analyzed from Rag-deficient mice.
Figure 4
Figure 4
CD4/CD8 subsets in the thymi of Pim1-transgenic mice lacking either γc (D) or the IL-7 (C) cytokine. Thymocytes from the indicated mice were analyzed for the relative size of CD4- and/or CD8-expressing thymocyte fractions. For comparison, the LckF (A) and Bcl2 (B) transgenes were also introduced into the γc-deficient background. Whereas LckF promotes differentiation of DN into DP thymocytes irrespective of cytokine signaling, only PIM1 was capable of increasing the absolute numbers of thymocytes in the absence of IL-7– or γc-dependent cytokine signaling (see Table ). wt, wild type.
Figure 5
Figure 5
PIM1 induces β-selection in Rag-deficient mice. Four-color FACS™ analysis on Pim1-transgenic thymocytes. Genotypes are given above each dot plot. Numbers within the quadrants indicate percentages. The lower half reveals the CD44/CD25 expression pattern of DP (third panel from left) and DN (fourth panel from left) thymocytes. Circles in the top panels indicate the gating on DN and DP thymocytes. In Rag2-deficient mice, Pim1 induces β-selection, giving rise to a subset of CD25−44− DN thymocytes, which develop into small CD25−44− DP thymocytes.
Figure 6
Figure 6
PIM1-induced β-selection in Rag-deficient mice is age dependent and lacking in CD3γ-mutant mice. (A) At an age of 8–9 wk, Pim1-transgenic/Rag2-mutant mice have formed a normally sized DP thymocyte compartment. (B) In CD3γ-mutant mice, however, even after 8 wk, Pim1 was incapable of increasing the number of DP thymocytes. Genotypes are indicated above each dot plot. Numbers within the quadrants indicate percentages. See also Table for absolute numbers.
Figure 6
Figure 6
PIM1-induced β-selection in Rag-deficient mice is age dependent and lacking in CD3γ-mutant mice. (A) At an age of 8–9 wk, Pim1-transgenic/Rag2-mutant mice have formed a normally sized DP thymocyte compartment. (B) In CD3γ-mutant mice, however, even after 8 wk, Pim1 was incapable of increasing the number of DP thymocytes. Genotypes are indicated above each dot plot. Numbers within the quadrants indicate percentages. See also Table for absolute numbers.
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