Abstract
Background: CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5+ IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5+ B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5+ B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5+ B cell expansion remains untested. Results: Using three different transgenic mouse models of benign or leukemic CD5+ B cell expansion, we found that CD1d was differentially expressed on CD5+ B cells between the three models, but loss of CD1d expression had no effect on CD5+ B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4+ and CD8+ T cells and an inverted CD4+:CD8+ T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts. Conclusions: The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5+ B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5+ B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8+ T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8+ T cells.
| Original language | English |
|---|---|
| Article number | 66 |
| Journal | BMC Immunology |
| Volume | 16 |
| Issue number | 1 |
| DOIs | |
| State | Published - Nov 4 2015 |
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All Science Journal Classification (ASJC) codes
- Immunology
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Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5+ B cell expansion. / Palmer, Victoria L.; Nganga, Vincent K.; Rothermund, Mary E.; Perry, Greg A.; Swanson, Patrick.
In: BMC Immunology, Vol. 16, No. 1, 66, 04.11.2015.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Cd1d regulates B cell development but not B cell accumulation and IL10 production in mice with pathologic CD5+ B cell expansion
AU - Palmer, Victoria L.
AU - Nganga, Vincent K.
AU - Rothermund, Mary E.
AU - Perry, Greg A.
AU - Swanson, Patrick
PY - 2015/11/4
Y1 - 2015/11/4
N2 - Background: CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5+ IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5+ B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5+ B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5+ B cell expansion remains untested. Results: Using three different transgenic mouse models of benign or leukemic CD5+ B cell expansion, we found that CD1d was differentially expressed on CD5+ B cells between the three models, but loss of CD1d expression had no effect on CD5+ B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4+ and CD8+ T cells and an inverted CD4+:CD8+ T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts. Conclusions: The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5+ B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5+ B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8+ T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8+ T cells.
AB - Background: CD1d is a widely expressed lipid antigen presenting molecule required for CD1d-restricted invariant natural killer T (iNKT) cell development. Elevated CD1d expression is detected in CD5+ IL10-producing B cells, called B10 B cells, and is correlated with poorer prognosis in chronic lymphocytic leukemia (CLL), a CD5+ B cell malignancy with B10-like functional properties. Whether CD1d expression regulates CD5+ B cell accumulation, IL10 competence, and antibody production in naïve mice with pathologic CD5+ B cell expansion remains untested. Results: Using three different transgenic mouse models of benign or leukemic CD5+ B cell expansion, we found that CD1d was differentially expressed on CD5+ B cells between the three models, but loss of CD1d expression had no effect on CD5+ B cell abundance or inducible IL10 expression in any of the models. Interestingly, in the CLL-prone Eμ-TCL1 model, loss of CD1d expression suppressed spontaneous IgG (but not IgM) production, whereas in the dnRAG1xEμ-TCL1 (DTG) model of accelerated CLL, loss of CD1d expression was associated with elevated numbers of splenic CD4+ and CD8+ T cells and an inverted CD4+:CD8+ T cell ratio. Unexpectedly, before leukemia onset, all three transgenic CD1d-deficient mouse strains had fewer splenic transitional B cells than their CD1d-proficient counterparts. Conclusions: The results show that CD1d expression and iNKT cells are dispensable for the development, accumulation, or IL10 competence of CD5+ B cells in mice prone to benign or leukemic CLL-like B cell expansion, but reveal a novel role for iNKT cells in supporting B cell progression through the transitional stage of development in these animals. These results suggest CD1d-directed therapies to target CLL could be evaded by downregulating CD1d expression with little effect on continued leukemic CD5+ B cell survival. The data also imply that iNKT cells help restrain pro-leukemic CD8+ T cell expansion in CLL, potentially explaining a reported correlation in human CLL between disease progression, the loss of NKT cells, and a paradoxical increase in CD8+ T cells.
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UR - http://www.scopus.com/inward/citedby.url?scp=84946206567&partnerID=8YFLogxK
U2 - 10.1186/s12865-015-0130-z
DO - 10.1186/s12865-015-0130-z
M3 - Article
C2 - 26537916
AN - SCOPUS:84946206567
VL - 16
JO - BMC Immunology
JF - BMC Immunology
SN - 1471-2172
IS - 1
M1 - 66
ER -