Memory T cell RNA rearrangement programmed by heterogeneous nuclear ribonucleoprotein hnRNPLL.
Differentiation of memory cells involves DNA-sequence changes in B lymphocytes but is less clearly defined in T cells. RNA rearrangement is identified here as a key event in memory T cell differentiation by analysis of a mouse mutation that altered the proportions of naive and memory T cells and crippled the process of Ptprc exon silencing needed to generate CD45RO in memory T cells. A single substitution in a memory-induced RNA-binding protein, hnRNPLL, destabilized an RNA-recognition domain that bound with micromolar affinity to RNA containing the Ptprc exon-silencing sequence. Hnrpll mutation selectively diminished T cell accumulation in peripheral lymphoid tissues but not proliferation. Exon-array analysis of Hnrpll mutant naive and memory T cells revealed an extensive program of alternative mRNA splicing in memory T cells, coordinated by hnRNPLL. A remarkable overlap with alternative splicing in neural tissues may reflect a co-opted strategy for diversifying memory T cells.
Wu
Zuopeng
Z
John Curtin School of Medical Research, Australian Phenomics Facility, Australian National University, Canberra ACT 0200, Australia.
Jia
Xinying
X
de la Cruz
Laura
L
Su
Xun-Cheng
XC
Marzolf
Bruz
B
Troisch
Pamela
P
Zak
Daniel
D
Hamilton
Adam
A
Whittle
Belinda
B
Yu
Di
D
Sheahan
Daniel
D
Bertram
Edward
E
Aderem
Alan
A
Otting
Gottfried
G
Goodnow
Christopher C
CC
Hoyne
Gerard F
GF
D017398:Alternative Splicing / Q000235:genetics*; D000595:Amino Acid Sequence; D000818:Animals; D005091:Exons / Q000235:genetics*; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007156:Immunologic Memory / Q000235:genetics*; D017493:Leukocyte Common Antigens / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012313:RNA / Q000235:genetics* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D034441:Heterogeneous-Nuclear Ribonucleoproteins; D020033:Protein Isoforms; C534662:hnRNPLL protein, mouse; D012313:RNA; D017493:Leukocyte Common Antigens