Membrane Lymphotoxin Is Required for the Development of Different Subpopulations of NK T Cells

The transmembrane protein tyrosine phosphatase CD45 is differentially required for the development and function of B, T, and NK cells, with mice partially deficient for CD45 having a significant inhibition of T cell, but not NK or B cell, development. CD45-mediated signaling has also been implicated in the development of intrathymic, but not extrathymic, intestinal intraepithelial T lymphocytes (iIELs) in the CD45ex6−/− mouse. As NK1.1+ CD3+ (NK-T) cells can also develop through extrathymic pathways, we have investigated the role of CD45 in NK-T cell development. In mice with a complete absence of CD45 expression (CD45ex9−/−) the NK-T cell population was maintained in the iIEL compartment, but not in the spleen. Functionally, CD45-deficient NK-T cells were unable to secrete IL-4 in response to TCR-mediated signals, a phenotype similar to that of CD45-deficient iIELs, in which in vitro cytokine production was dramatically reduced. Using the CD45ex9−/− mouse strain, we have also demonstrated that only one distinct population of NK-T cells (CD8+) appears to develop normally in the absence of CD45. Interestingly, although an increase in cytotoxic NK cells is seen in the absence of CD45, these NK calls are functionally unable to secrete IFN-γ. In the absence of CD45, a significant population of extrathymically derived CD8αα+ iIELs is also maintained. These results demonstrate that in contrast to conventional T cells, CD45 is not required during the development of CD8+ NK-T cells, NK cells, or CD8αα+ iIELs, but is essential for TCR-mediated function and cytokine production.

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“…ϩ or CD4 Ϫ CD8 Ϫ , in agreement with previous reports (Table I) (7,42). Surprisingly, however, as is shown in Table I and Fig.…”

Section: Cells Were Cd4supporting

confidence: 93%

Development of Intestinal Intraepithelial Lymphocytes, NK Cells, and NK 1.1+ T Cells in CD45-Deficient Mice

Martin

Mehta²,

Yokoyama

et al. 2001

The Journal of Immunology

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“…These mice have significantly reduced levels of Aire [20] and NKT cells [21,22], but relatively normal conventional T-cell numbers. A similar correlation between Aire expression and NKT cell numbers was reported in lymphotoxin-deficient mice [23,24], although the link between the expression of lymphotoxin and Aire-dependent genes has been disputed in more recent studies [25][26][27]. Human patients (and a mouse model) of Omenn syndrome [28,29] also have reduced levels of Aire and NKT cells and it is interesting to note that the severe NKT cell deficit evident in NOD mice coincides with significant morphological abnormalities among Aire 1 medullary cells in the thymus [20].…”

Section: Introductionsupporting

confidence: 75%

NKT cell development in the absence of the autoimmune regulator gene (Aire)

et al. 2008

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Autoimmune regulator gene (Aire)-deficient mice develop an array of autoimmune lesions that reflect failures of immune tolerance. Negative selection is clearly compromised in these mice, but there is evidence to suggest that other mechanisms of tolerance might also be affected, including a possible impairment of regulatory T cell (Treg) development. Studies to date have failed to demonstrate any significant impact on the development or function of the FOXP3 1 Treg compartment, but NKT cells represent a distinct regulatory cell lineage that also develop in the thymus and which are known to influence selftolerance. Aire-related defects coincide with NKT cell deficiencies in a number of animal models, but the direct consequence of Aire-deficiency on NKT cell development has not been established. In this study, we demonstrate that the frequency, distribution and cytokine production of NKT cells and their subsets is principally normal in Aire-deficient mice. We conclude that Aire has little or no effect on regulatory T cell development in general and NKT cells in particular.

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“…Consistent with these findings, cytokine production levels induced by in vivo immunization with the glycolipid ␣-GalCer were found to be reduced in LT␣ 0/0 , LT␤ 0/0 , and LT␤R 0/0 mice but not in LIGHT 0/0 mice (ref. 24 and unpublished data). Nevertheless, the ability of the residual V␣14i NKT cells to produce IFN-␥ (Fig.…”

Section: Reduction Of V␣14i Nkt Cells In Peripheral Organs But Not Tmentioning

confidence: 68%

A unique lymphotoxin αβ-dependent pathway regulates thymic emigration of Vα14 invariant natural killer T cells

Franki

Beneden²,

Dewint³

et al. 2006

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

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Natural killer (NK) T cells using an invariant V␣14 (V␣14i) T cell receptor rearrangement form a distinct immunoregulatory T cell lineage. Several studies indicated that a NK1.1 ؊ V␣14i NKT precursor cell differentiates and expands within the thymus before export to the peripheral tissues occurs. However, little is known about the signals that cause the emigration of V␣14i NKT cells from the thymus to the periphery. Here we show that signaling of lymphotoxin (LT) ␣␤ through the LT␤ receptor (LT␤R) is indispensable for regulating peripheral but not thymic V␣14i NKT cell numbers. Homing to and homeostatic proliferation of thymic V␣14i NKT cells in peripheral organs, however, was not dependent on LT␤R. Instead, our data indicate that a LT␤R-expressing thymic stromal cell regulates the thymic emigration of V␣14i NKT cells but not conventional T cell receptor ␣␤ cells.ymphotoxin (LT) ␣ and ␤ are members of the TNF family that form biologically active homotrimers or heterotrimers. LT␣ can be secreted as a homotrimer that can bind with equal affinity to either TNF receptor 1 or 2 (1). LT␣ can also be membrane-bound by association with LT␤ to form LT␣␤ (2, 3). This heterotrimer binds exclusively to another receptor, the LT␤ receptor (LT␤R), which is expressed on nonlymphoid cells (4). Over the past years, a wealth of data has indicated an indispensable role for the LT␣␤-LT␤R interaction in secondary lymphoid organ structure development and function (5, 6). In addition, some studies have shown a functional impairment in generating secondary antibody responses to certain antigens in LT-deficient mice, although normal numbers of T and B cells are found (7,8).Natural killer (NK) T cells recognize glycolipid antigens (9, 10), and they form a unique lymphocyte subset with important immunoregulatory properties (11). They coexpress NK receptors and intermediate levels of T cell receptor (TCR) ␣␤ and have a phenotype reminiscent of activated T cells. Several distinct subsets of NKT cells have been described (12). In mice the most abundant NKT cell subpopulation is characterized by an invariant TCR␣ rearrangement, V␣14-J␣18, and is reactive with CD1d, a nonclassical class I antigen-presenting molecule (13,14). We will hereafter refer to these cells as V␣14 invariant (V␣14i) NKT cells. Upon recognition of the synthetic glycolipid ␣-galactosylceramide (␣-GalCer), which is presented by CD1d (10), TCR stimulation results in the rapid production of proinflammatory cytokines that influence other immune cells, including NK cells, dendritic cells, and B and T cells (11).There is evidence that V␣14i NKT cells form a separate T cell lineage because they are selected in the thymus by a hematopoietic cell type, which contrasts with the selection of conventional T cells by thymic epithelial cells (15)(16)(17)(18). With the availability of ␣-GalCer-loaded CD1d tetramers (19), important new information has been obtained about V␣14i NKT cell ontogeny, showing that NK1.1 receptor expression is modulated during development, meaning that not all V␣...

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Membrane Lymphotoxin Is Required for the Development of Different Subpopulations of NK T Cells

Cited by 59 publications

References 64 publications

Development of Intestinal Intraepithelial Lymphocytes, NK Cells, and NK 1.1+ T Cells in CD45-Deficient Mice

Development of Intestinal Intraepithelial Lymphocytes, NK Cells, and NK 1.1+ T Cells in CD45-Deficient Mice

NKT cell development in the absence of the autoimmune regulator gene (Aire)

A unique lymphotoxin αβ-dependent pathway regulates thymic emigration of Vα14 invariant natural killer T cells

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