LncRNAs in adaptive immunity: role in physiological and pathological conditions

Figures & data

Figure 1. Schematic overview of lncRNAs’ mechanisms of action. LncRNA can a) promote or disrupt signal transduction by interacting with proteins, b) serve as a scaffold to proteins, c) act as competing endogenous RNAs (ceRNA) and bind miRNAs, d) guide or e) decoy transcription factors

Table 1. Summary of lncRNAs involved in T cell biology

LncRNA name (alternative name)	Function	Ref.
NALT1 (MIR4674HG, LINC01573)	Cis-regulates NOTCH1 expression	[29]
LUNAR1 (lnc-IGF1R-1)	Cis-regulates IGF1R expression	[122]
PVT1 (MIR1204HG, LINC00079)	Involved in the glycolytic pathway	[33]
NRON (NCRNA00194, lnc-ANGPTL2-10)	Impairs NFAT activity	[36–38]
NKILA	Represses NFκB activity	[40]
IFNG-AS1 (Nest, Tmevpg1, lincR-Ifng-3ʹAS)	Enhances IFNγ production	[42,43,51,96]
lncRNA-AS-GSTT1(lncRNA- BC050410, lncRNA-CD244)	Transcription repression of IFNγ and TNFα via EZH2	[46]
Morrbid (MIR4435-2HG, CYTOR, AGD2, LINC00978, lncRNA-AWPPH)	Impairs IFNγ production	[47]
GATA3-AS1	Promotes chromatin remodelling via WDR5	[54]
TH2-LCR	Promotes chromatin remodelling via WDR5	[55]
LincR-Crr2-5ʹAS	Enhances the expression of chemokines Ccr1/2/3/5	[14]
linc-MAF4	Transcription repression of c-MAF via LSD1 and EZH2	[49,50]
lncRNA MEG3 (GTL2, LINC00023)	ceRNA for miR-17 which targets RORγt	[58]
Lnc-DDIT4	Cis-activates DDIT4 and enhances mTOR activity	[63]
NEAT1 (LINC00084, VINC)	Promotes stabilization of STAT3, ceRNA for miR-155 which targets TIM-3	[61,146]
GAS5 (SNHG2)	Promotes the degradation of STAT3	[62]
Flatr	Role in TREG polarization	[64]
Lnc-Smad3	Transcription repression of SMAD3 via HDAC1	[66]
Linc-POU3F3 (PANTR1, LINC01158, linc-Brn1a)	Enhances TGFβ pathway	[65]
Flicr	Cis regulates FOXP3	[68]
lncRNA-EGFR	Binds and prevents EGFR degradation via cCBL	[70]
Lnc-TIM3	Binds TIM-3 to disrupt TCR signalling	[147]

Figure 2. Summary of lncRNAs’ regulatory networks involved in T cell biology. LncRNAs influence T cell activation and inhibition by participating in TCR cascade and T cell inhibition through co-inhibitory receptor signals (centre of the figure top and bottom). LncRNAs are also involved in differentiating T_H subsets and their effector functions (such as T_H17, T_REG, T_H1, T_H2; see corners of the figure for each subset). These lncRNAs can dictate T_H polarization upon TCR activation and contribute to T cell response. LncRNAs are indicated in bold boxes, miRNAs in rectangles, and proteins or functions in other boxes. Arrows indicate positive regulation, blunt-ended lines indicate negative regulation, and straight lines indicate interaction. Gene names in red indicate typical markers for each subset of the T_H population

Table 2. Summary of lncRNAs involved in B cell biology

LncRNA name (alternative name)	Function	Ref.
BCALM (AC099524.1)	Promotes a negative feedback loop in BCR-mediated calcium signalling	[73]
XIST (LINC00001, DXS1089, DXS399E, NCRNA00001)	Heterochromatin modifications	[76,77]
RP11-132N15.3	Correlates with BCL6 expression	[27]
RP11-211G3.3.1–1 (BCL6-AS1)	Antisense lncRNA of the BCL6 gene	[80]
lncRNA-CSR^IgA	Promotes IgA class switch	[87]
Linc00525	Correlates with plasma cells response	[91]
GUSBP11	Correlates with plasma cells response	[91]
FAM30A (C14orf110, HSPC053, KIAA0125)	Correlates with plasma cells response and antibody titres	[91, 92]
BRAFP1/Braf-rs1	ceRNA; promotes BRAF expression and MAPK activation	[115]
HMGA1P	ceRNA; dysregulates NFκB pathway, IL6/JAK/STAT3 axis, mTOR signalling, MYC, and others	[116]
DLEU1/2	Host genes for miR-15/16 and cis-regulate NFκB-related genes	[129]
FIRRE (LINC01200)	Activates Wnt/β pathway	[132]
DANCR (AGU2, ANCR, KIAA0114, SNHG13, lncRNA-ANCR)	Inhibits p21 and influences in cell proliferation	[133]
PDIA3P (GRP58P, PDIA3P1)	Involved in pentose phosphatase pathway	[134]
RMRP (CHH, NME1, RMRPR, RRP2)	ceRNA for miR-34-5p	[135]
GAS5 (NCRNA00030, SNHG2)	Negatively regulates MYC translation	[136]
ROR1-AS1	Regulates gene transcriptions via PRC2 complex to promote cell growth	[141]
MALAT1 (HCN, LINC00047, NCRNA00047, NEAT2, PRO1073, mascRNA)	Regulates gene transcriptions via PRC2 complex to promote cell growth	[142]
FAS-AS1	Regulate Fas isoforms and Fas-mediated apoptosis	[143]
NEAT1 (LINC00084, VINC)	DNA damage response and inducible cell death	[144]
LincRNA-p21 (TRP53COR1)	DNA damage response and inducible cell death	[144]

Figure 3. Summary of lncRNAs’ involvement in B cell biology. a) BCALM and DLEU1/2 are involved in B cell activation. BCALM drives a negative feedback loop with SHP1 to decrease BCR-mediated activation while DLEU1/2 cis-regulates NFκB-related genes. b) LncRNAs can promote malignant B cell proliferation by interacting with EZH2 and by being a part of MYC’s pro-proliferative program. c) FAS-AS1 promotes membrane Fas isoform generation. FAS-AS1 is epigenetically repressed in B cell lymphomas, leading to soluble Fas generation and cell death evasion. d) NEAT1 and lincRNA-p21 are regulated by p53 during DNA damage response. e) During germinal centre (GC) reaction, AID interacts with xTSS-RNAs that influence genome integrity. AID also binds transcripts from the S region to drive class switch recombination and lncRNA-CSR^IgA specifically induces an IgA class switch. f) FAM30A is an antisense RNA from the IgH locus that positively correlates with high antibody titres. Plasma cells generate high levels of circRNAs from Ig genes. LncRNAs are indicated in bold boxes, miRNAs in rectangles, and proteins or pathways in other boxes. Arrows indicate positive regulation, blunt-ended lines indicate negative regulation, and straight lines indicate interaction. DSB, double-strand break; CSR, class switch recombination

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