Abstract
Retinoid X receptor (RXR) agonists, including the vitamin A metabolite 9-cis retinoic acid, decrease T-lymphocyte apoptosis and promote T helper type 2 (Th2) development ex vivo. To examine the in vivo role of RXR-α in T-lymphocyte development and function, we disrupted the Rxra gene in thymocytes and T lymphocytes using cyclization recombinase (Cre)-loxP-mediated excision of Rxra exon 4. Expression of Cre was targeted to these cells using the Lck promoter. Successful disruption of exon 4 was seen in thymus and T lymphocytes. Mice were healthy and the thymus, spleen and lymph nodes appeared normal. However, knockout mice had a lower percentage of double-positive (CD4 + CD8+) and a higher percentage of double-negative thymocytes than wild-type mice. The percentage of splenic B lymphocytes was lower in unimmunized and ovalbumin-immunized knockout mice and the percentage of T lymphocytes was lower in immunized knockout mice. Ex vivo proliferation was decreased and apoptosis was increased in T lymphocytes from knockout mice. Memory CD4+ T lymphocytes from knockout mice produced more interferon-γ and interleukin-2 (IL-2) and less IL-5 and IL-10 than memory cells from wild-type mice, indicating a Th1 bias in vivo. However, Rxra disruption did not similarly bias ex vivo differentiation of naive CD4 + T lymphocytes, nor did Rxra disruption alter the serum immunoglobulin G1/immunoglobulin G2a response to immunization. In summary, disruption of Rxra altered the percentages of T and B lymphocytes, produced a Th1 bias in vivo, and altered T-lymphocyte proliferation and apoptosis ex vivo. These differences were modest in magnitude and their impact on disease resistance is yet to be examined.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 484-498 |
| Number of pages | 15 |
| Journal | Immunology |
| Volume | 121 |
| Issue number | 4 |
| DOIs | |
| State | Published - Aug 2007 |
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Keywords
- Knockout mice
- Retinoid X receptor-α
- T helper type 1/T helper type 2
- T lymphocyte
- Vitamin A
ASJC Scopus subject areas
- Immunology
Cite this
Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance. / Stephensen, Charles B.; Borowsky, Alexander D; Lloyd, Kevin C K.
In: Immunology, Vol. 121, No. 4, 08.2007, p. 484-498.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Disruption of Rxra gene in thymocytes and T lymphocytes modestly alters lymphocyte frequencies, proliferation, survival and T helper type 1/type 2 balance
AU - Stephensen, Charles B.
AU - Borowsky, Alexander D
AU - Lloyd, Kevin C K
PY - 2007/8
Y1 - 2007/8
N2 - Retinoid X receptor (RXR) agonists, including the vitamin A metabolite 9-cis retinoic acid, decrease T-lymphocyte apoptosis and promote T helper type 2 (Th2) development ex vivo. To examine the in vivo role of RXR-α in T-lymphocyte development and function, we disrupted the Rxra gene in thymocytes and T lymphocytes using cyclization recombinase (Cre)-loxP-mediated excision of Rxra exon 4. Expression of Cre was targeted to these cells using the Lck promoter. Successful disruption of exon 4 was seen in thymus and T lymphocytes. Mice were healthy and the thymus, spleen and lymph nodes appeared normal. However, knockout mice had a lower percentage of double-positive (CD4 + CD8+) and a higher percentage of double-negative thymocytes than wild-type mice. The percentage of splenic B lymphocytes was lower in unimmunized and ovalbumin-immunized knockout mice and the percentage of T lymphocytes was lower in immunized knockout mice. Ex vivo proliferation was decreased and apoptosis was increased in T lymphocytes from knockout mice. Memory CD4+ T lymphocytes from knockout mice produced more interferon-γ and interleukin-2 (IL-2) and less IL-5 and IL-10 than memory cells from wild-type mice, indicating a Th1 bias in vivo. However, Rxra disruption did not similarly bias ex vivo differentiation of naive CD4 + T lymphocytes, nor did Rxra disruption alter the serum immunoglobulin G1/immunoglobulin G2a response to immunization. In summary, disruption of Rxra altered the percentages of T and B lymphocytes, produced a Th1 bias in vivo, and altered T-lymphocyte proliferation and apoptosis ex vivo. These differences were modest in magnitude and their impact on disease resistance is yet to be examined.
AB - Retinoid X receptor (RXR) agonists, including the vitamin A metabolite 9-cis retinoic acid, decrease T-lymphocyte apoptosis and promote T helper type 2 (Th2) development ex vivo. To examine the in vivo role of RXR-α in T-lymphocyte development and function, we disrupted the Rxra gene in thymocytes and T lymphocytes using cyclization recombinase (Cre)-loxP-mediated excision of Rxra exon 4. Expression of Cre was targeted to these cells using the Lck promoter. Successful disruption of exon 4 was seen in thymus and T lymphocytes. Mice were healthy and the thymus, spleen and lymph nodes appeared normal. However, knockout mice had a lower percentage of double-positive (CD4 + CD8+) and a higher percentage of double-negative thymocytes than wild-type mice. The percentage of splenic B lymphocytes was lower in unimmunized and ovalbumin-immunized knockout mice and the percentage of T lymphocytes was lower in immunized knockout mice. Ex vivo proliferation was decreased and apoptosis was increased in T lymphocytes from knockout mice. Memory CD4+ T lymphocytes from knockout mice produced more interferon-γ and interleukin-2 (IL-2) and less IL-5 and IL-10 than memory cells from wild-type mice, indicating a Th1 bias in vivo. However, Rxra disruption did not similarly bias ex vivo differentiation of naive CD4 + T lymphocytes, nor did Rxra disruption alter the serum immunoglobulin G1/immunoglobulin G2a response to immunization. In summary, disruption of Rxra altered the percentages of T and B lymphocytes, produced a Th1 bias in vivo, and altered T-lymphocyte proliferation and apoptosis ex vivo. These differences were modest in magnitude and their impact on disease resistance is yet to be examined.
KW - Knockout mice
KW - Retinoid X receptor-α
KW - T helper type 1/T helper type 2
KW - T lymphocyte
KW - Vitamin A
UR - http://www.scopus.com/inward/record.url?scp=34447101951&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=34447101951&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2567.2007.02595.x
DO - 10.1111/j.1365-2567.2007.02595.x
M3 - Article
C2 - 17433077
AN - SCOPUS:34447101951
VL - 121
SP - 484
EP - 498
JO - Immunology
JF - Immunology
SN - 0019-2805
IS - 4
ER -