CN109468326A - A kind of CD4+T aptamer and its application - Google Patents
A kind of CD4+T aptamer and its application Download PDFInfo
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Abstract
The present invention discloses a kind of CD4 T aptamer and its application, belongs to genetic engineering, immunology and oncology technical field.The aptamers are one or several any sequence in nucleotide sequence shown in NO:1 ~ 5 SEQ ID.Aptamer of the present invention is obtained using living cells abatement Cell-SELEX technology screening, and molecular weight is smaller, is readily synthesized and modifies, can high specific identification and high-affinity combination CD4 T, in conjunction with other cells not occurrence features, non-immunogenicity, stablize easily modification, convenient for synthesis and saves.The CD4 T detection kit and reagent paper prepared with the aptamers is high to CD4 T detection sensitivity, and is easy to optimize.It is applied in diagnosing tumor, tumor prognosis and the assessment of monitoring, diagnosing tumor.
Description
Technical field
The invention belongs to genetic engineering, immunology and oncology technical field, in particular to a kind of CD4 T aptamer
And its application.
Background technique
Malignant tumour has become the principal disease in the harm whole world, seriously endangers the health of the mankind.Liver cancer is common original
One of hair property malignant tumour, lethality arrange global malignant tumour lethality third position.Most of patients passes through chemotherapy, radiotherapy at present
And the method for operation treats tumour, but effect is still to be improved, and tumour immunity targeted therapy as completely new treatment mode just
Gradually it is accepted by people.In recent years, effect of the CD4 T cell of activation in anti tumor immune response is increasingly by people
Attention.It not only has the function of immunological memory and direct killing tumour cell, but also can assist CD8+ T cell is to swollen
The killing of oncocyte.But because its activity is bad and lacks targeting, limit its application clinically.Therefore, double spies are utilized
The CD4 T cell of anisotropic aptamers effectively mediated activation is targeted to tumor by local, improves the antitumor effect of cellular immunotherapy
Fruit will provide a new therapeutic strategy for the application of cellular immunotherapy clinically.
Aptamer is the obtained truncated single stranded DNA (single- being used in conjunction with particular target by screening
Stranded DNA, ssDNA) or RNA molecule, have and be readily synthesized, immunogenicity is lower, molecular weight small (10-15kDa) etc.
Advantage.Because have with effect as antibody class, be otherwise known as " chemical antibody ".The appearance of aptamer is that chemistry is raw
Object educational circles and biomedical boundary provide a kind of new identification facility, and good answer especially is illustrated in terms of hepatocarcinoma early diagnosis
Use prospect.There has been no the reports of CD4 T aptamers screening at present, if the adaptation that can specifically bind CD4 T can be filtered out
Body provides broader platform without the detection suspected of CD4 T.
CD4 T cell as helper T lymphocyte, can in auxiliary body panimmunity cell antitumor action.It auxiliary
Help effect for CD8+ The activation stage of T cell is required.CD4 T cell secrete cytokines IL-2 etc. and can promote
APCs expresses the costimulatory molecules such as B7, assists CD8+ The activation of T cell, to CD8+ Activation, proliferation and the differentiation tool of T cell
It is of great significance.CD4 T cell can assist in activation B cell simultaneously and generate antibody, stimulate CD8+ T cell secretion
IFN-γ, activating macrophage, and enhance NK cell activity, improve the anti-tumor capacity of body immune system.CD4 T cell energy
Enough promote the generation of memory cells toxic cell (CTL) and maintain long-term Memory CTL response, and CD4 T cell pair
In maintenance and promote CD8+ The memory immune response of T cell also plays a very important role.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of CD4 T aptamer and its applications.
Technical solution used in purpose to realize the present invention are as follows:
A kind of CD4 T aptamer, the aptamers are any in nucleotide sequence shown in NO:1 ~ 5 SEQ ID
One or several sequence.
Preferably, the aptamers have with any one in nucleotide sequence shown in NO:1 ~ 5 SEQ ID or
The sequence that the homology of several sequences is 60% or more.
Preferably, the aptamers have with any one in nucleotide sequence shown in NO:1 ~ 5 SEQ ID or
The sequence that several sequences are hybridized.
Preferably, the aptamers have with any one in nucleotide sequence shown in NO:1 ~ 5 SEQ ID or
The sequence that several sequences are transcribed.
Preferably, several positions in the aptamers sequence be phosphorylated, methylate, amination, sulfhydrylation or
Isotopologue.
Preferably, it is combined with biotin in the aptamers sequence, digoxin, fluorescent material, nano luminescent material, gathers
Ethylene glycol, peptide fragment, albumen, folic acid or enzyme label.
Preferably, the CD4 T aptamer has and appointing in nucleotide sequence shown in NO:1 ~ 5 SEQ ID
Anticipate one or several sequence alterations at corresponding peptide nucleic acid.
The present invention also provides a kind of CD4 T aptamers to prepare answering for CD4 T detection kit or detection reagent paper
With.
Present invention substantive distinguishing features outstanding and significant progress are:
Aptamer of the present invention is obtained using full Cell depletion Cell-SELEX technology screening, and molecular weight is smaller, is readily synthesized
With modification, can high specific identification and high-affinity combination CD4 T, with other bacteriums not occurrence features ining conjunction with, nothing be immunized
Originality stablizes easily modification, convenient for synthesis and saves, can be used for detecting CD4+T, and effectively prevent and control CD4 T, have
Significance.The CD4 T detection kit and reagent paper prepared with the aptamers is high to CD4 T detection sensitivity, and is easy to
Optimization.
Detailed description of the invention
Fig. 1 is the flow cytometer detection result of activation degree of the Naive CD4 T cell through ConA stimulation front and back.
Fig. 2 is the combination of the CD4 T cell and Naive CD4 T cell of flow cytometer monitoring enriched library and activation
Ability；A. streaming result of each wheel screening enrichment library in conjunction with the CD4 T cell of activation；B. each wheel screening enrichment library with
The streaming result that Naive CD4 T cell combines.
Fig. 3 is the streaming of different cells situation in conjunction with candidate aptamers as a result, detection cell is respectively the CD4 activated
T cell (A), Naive CD4 T cell (B), BNL.CL2 cell (C), bsr cell (D), DC2.4 cell (E) and 3T3 are thin
Born of the same parents (F).
Fig. 4 is the CD4 T cell (A) and Naive CD4 T cell of Act-12a, Act-12b and Act-12c and activation
(B) combination situation.
Fig. 5 is fluorescence imaging result of the Act-12c in conjunction with the CD4 T cell of activation and Naive CD4 T cell
(1000 x)。
Specific embodiment
The present invention program is described in further detail below with reference to embodiment, following the description is merely to explain this hair
It is bright, its content is not defined.
Embodiment
1 ConA stimulates Naive CD4 T to obtain the CD4 T cell activated
The present invention uses the CD4 T cell of the activation obtained through ConA stimulation Naive CD4 T cell as positive sieve cell,
Stimulated front and back activation degree is as shown in Figure 1, in Naive CD4 T cell before stimulating through ConA, the CD4 T cell of activation
(i.e. CD4+CD69+ T cell) it is 3.8 ± 1.3%, in the Naive CD4 T cell after ConA stimulates 48 h, the CD4 of activation
T cell is 84.9 ± 5.2%.This is the results show that the CD4 T cell of the activation obtained through ConA stimulation is thin as positive sieve
Born of the same parents have feasibility.
The 2 CD4 T cell aptamers activated using Cell-SELEX technology screening
SsDNA initial libraries and Naive CD4 T cell (counter-selection cell) are subjected to counter-selection selection operation first, discarding can be with counter-selection
The ssDNA of cell combination is gone unless aim sequence.Then, the not ssDNA with counter-selection cell combination, the CD4 T with activation are collected
Cell (positive sieve cell) is just being screened, and by the sequence of washing removal non-specific binding, collects energy and target cell specificity
In conjunction with ssDNA sequence and it is expanded using PCR, the secondary library that is formed after single stranded is handled investment next round
Screening.Enriched library is subjected to cloning and sequencing when enrichment reaches saturation when library according to above process repeated screening.Finally, logical
The level-one mechanism and secondary structure for crossing analytical sequence select several candidate aptamers and carry out Function Identification.
3 flow cytometries monitoring screening library enrichment degree
To judge screening process of the invention, the saturation state of enriched library is judged.By initial libraries and the 5th wheel, the 7th wheel, the
10 wheels, 11th round screen Product Labeling FITC fluorescence, are incubated for respectively with positive sieve cell, counter-selection cell, then carry out streaming
Cell art detection.As a result as shown in Fig. 2, with number of screening round increase, enriched library is in conjunction with the CD4 T cell of activation
Fluorescence curve gradually deviates to the right, and fluorescence intensity gradually increases, and the fluorescence curve of 11th round is compared with the fluorescence curve of the 10th wheel
Degrees of offset is very faint to the right, and when indicating screening to 11th round, enriched library has tended to saturation state.And each round screening text
There is no apparent shift phenomenon to the right occurs for fluorescence curve of the library in conjunction with Naive CD4 T cell.Show that screening has reached
Terminal, 11th round enriched library can be in conjunction with target cells, without in conjunction with control cell.
The secondary structure analysis of 4 sequencing results
Due to the combination of aptamers and target cell be based on the special three-dimensional structure of aptamers sequence in conjunction with the space of target cell,
Therefore its secondary structure largely determines the binding ability of aptamers and target.The present invention respectively chooses from five families
Select a repetitive rate high candidate aptamers Act-4, Act-5, Act-12, Act-15 and Act-20.Utilize NUPACK
(http://www.nupack.org) is simulated the secondary structure of candidate aptamers.Candidate aptamers sequence such as 1 institute of table
Show.
The candidate aptamers sequence of table 1
| Title | Sequence (5 ' -3 ') |
| Act-4 | ATACCAGCTTATTCAATTCATCCGCAACTTTGCCCCTCCACTCCCCTATCTCCTTTCGCCATCAGATAGTAAGTGCAATCT |
| Act-5 | ATACCAGCTTATTCAATTCGCCAAACCCGGATTTTTTGTTTTCCCCTTTATAGTACCGTCACAAGATAGTAAGTGCAATCT |
| Act-12 | ATACCAGCTTATTCAATTCGGGGAAAGTCACGGGGGGTTTCAGATGTTCTGATCGGTGTGGAGAGATAGTAAGTGCAATCT |
| Act-15 | ATACCAGCTTATTCAATTCGGGGAAAGTCACGGGGGGTTTCAGATGTTCTGATCGGTGTGGAGAGATAGTAAGTGCAATCT |
| Act-20 | ATACCAGCTTATTCAATTCGGCGGCCGTGCTATAGCGGAGTCCCTTTTCTTCCCCCTATGTACAGAGATAGTAAGTGCAATCT |
The cell-specific analysis of 5 candidate aptamers
To investigate five candidate aptamers to the specific binding capacity of target cell, the present invention utilizes flow cytomery five
Item candidate aptamers are respectively and the combination situation of six kinds of cells.As a result as shown in figure 3, five candidate aptamers can be with activation
CD4 T cell (target cell) combines, and thin with control cell Naive CD4 T cell, BNL.CL2 cell, bsr cell, DC2.4
Born of the same parents and 3T3 cell do not combine.
The design of 6Act-12 optimization
The design of initial libraries according to the present invention, screen acquisition aptamers sequence Act-12 be 81bp, and and not all core
Thuja acid is involved in the identification of target cell, and extra nucleotide itself may be accumulated and form steric hindrance or the function with key
Nucleotide hybridizes, and then weakens the binding ability of aptamer.Therefore, it is necessary to carry out sequence truncation to Act-12
Optimization.By analyzing the primary structure and secondary structure of Act-12 sequence, its sequence is deleted, the sequence after optimization truncation
Column are as shown in table 2.
2 Act-12 of table optimizes truncated sequence
| Title | Sequence (5 ' -3 ') |
| Act-12 | ATACCAGCTTATTCAATTCGGGGAAAGTCACGGGGGGTTTCAGATGTTCTGATCGGTGTGGAGAGATAGTAAGTGCAATCT |
| Act-12a | CGGGGAAAGTCACGGGGGGTTTCAGATGTTCTGATCGGTGTGGAGAGATAGTAAGTGCAATCT |
| Act-12b | ATACCAGCTTATTCAATTCGGGGAAAGTCACGGGGGGTTTCAGATGTTCTGATCGGTGTGGAG |
| Act-12c | CGGGGAAAGTCACGGGGGGTTTCAGATGTTCTGATCGGTGTGGAG |
According to former sequence Act-12, three truncated sequences are devised.Act-12a is to delete upstream primer on the basis of former sequence
Sequence, sequence length is 63 bp after truncation；Act-12b is that downstream primer sequence is deleted in former sequence basis, sequence after truncation
Length is 63 bp；And Act-12c is to delete the upstream and downstream primer sequence at both ends, sequence length is 45 bp after truncation.
The optimization of 7 Act-12 can be in conjunction with the CD4 T cell of activation
In order to further investigate the binding ability of three aptamers sequences and target cell after truncating optimization, the present invention uses streaming
Cell art detects the combination situation of FITC Act-12a, Act-12b and Act-12c marked and target cell.As a result such as
Shown in Fig. 4, three aptamers sequences Act-12a, Act-12b and Act-12c through truncating optimization can be with target cells well
In conjunction with wherein Act-12c is not substantially change compared with the binding ability of target cell and former sequence Act-12.And Act-12a,
Act-12b and Act-12c is not combined with counter-selection cell.
8 Act-12c can be specifically bound with the CD4 T cell of activation
The FITC Act-12c marked is incubated for target cell and counter-selection cell respectively, uses confocal fluorescent microscopic pair
It combines situation to be observed.As a result after such as Fig. 5, Act-12c and the CD4 T cell of activation are incubated for, cell membrane surface has relatively strong
Green fluorescence expression, and with Naive CD4 T cell be incubated for after, there is no green fluorescence expression for cell membrane surface.Initial text
After library and control aptamers TLS9a are incubated for the CD4 T cell of activation and Naive CD4 T cell respectively, cell membrane surface is simultaneously
There is no green fluorescence expression.
The foregoing is only a preferred embodiment of the present invention, is not intended to restrict the invention, for the skill of this field
For art personnel, the invention may be variously modified and varied.It is done within the spirit and principles of the present invention any to repair
Change, equivalent replacement, improvement etc., should be included within scope of the invention.
Sequence table
<110>Guangxi Medical University
<120>a kind of CD4<sup>+</sup>t aptamer and its application
<130> 2018-5-31
<160> 5
<170> SIPOSequenceListing 1.0
<210> 1
<211> 81
<212> DNA
<213>artificial sequence (Artificial sequence Latin)
<400> 1
ataccagctt attcaattca tccgcaactt tgcccctcca ctcccctatc tcctttcgcc 60
atcagatagt aagtgcaatc t 81
<210> 2
<211> 81
<212> DNA
<213>artificial sequence (Artificial sequence Latin)
<400> 2
ataccagctt attcaattcg ccaaacccgg attttttgtt ttccccttta tagtaccgtc 60
acaagatagt aagtgcaatc t 81
<210> 3
<211> 81
<212> DNA
<213>artificial sequence (Artificial sequence Latin)
<400> 3
ataccagctt attcaattcg gggaaagtca cggggggttt cagatgttct gatcggtgtg 60
gagagatagt aagtgcaatc t 81
<210> 4
<211> 81
<212> DNA
<213>artificial sequence (Artificial sequence Latin)
<400> 4
ataccagctt attcaattcg gggaaagtca cggggggttt cagatgttct gatcggtgtg 60
gagagatagt aagtgcaatc t 81
<210> 5
<211> 83
<212> DNA
<213>artificial sequence (Artificial sequence Latin)
<400> 5
ataccagctt attcaattcg gcggccgtgc tatagcggag tcccttttct tccccctatg 60
tacagagata gtaagtgcaa tct 83
Claims (9)
1. a kind of CD4 T aptamer, which is characterized in that the aptamers are nucleosides shown in NO:1 ~ 5 SEQ ID
One or several any sequence in acid sequence.
2. CD4 T aptamer according to claim 1, which is characterized in that the aptamers have and SEQ ID
The sequence that the homology of one or several any sequence in nucleotide sequence shown in NO:1 ~ 5 is 60% or more.
3. CD4 T aptamer according to claim 1, which is characterized in that the aptamers have and SEQ ID
The sequence that one or several any sequence in nucleotide sequence shown in NO:1 ~ 5 is hybridized.
4. CD4 T aptamer according to claim 1, which is characterized in that the aptamers have and SEQ ID
The sequence that one or several any sequence in nucleotide sequence shown in NO:1 ~ 5 is transcribed.
5. CD4 T aptamer according to claim 1, which is characterized in that the aptamers have and SEQ ID
One or several any sequence in nucleotide sequence shown in NO:1 ~ 5 optimizes truncated sequence.
6. CD4 T aptamer according to claim 1, which is characterized in that several in the aptamers sequence
A position is phosphorylated, methylates, amination, sulfhydrylation or isotopologue.
7. CD4 T aptamer according to claim 1, which is characterized in that be combined in the aptamers sequence
Biotin, digoxin, fluorescent material, nano luminescent material, polyethylene glycol, peptide fragment, albumen, folic acid or enzyme label.
8. CD4 T aptamer according to claim 1, which is characterized in that the CD4 T aptamer has
With one or several any sequence alterations in nucleotide sequence shown in NO:1 ~ 5 SEQ ID at corresponding peptide nucleic acid.
9. CD4 T aptamer described in claim 1-7 any one is in preparation CD4 T detection kit or detection reagent paper
Application.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111004805A (en) * | 2019-12-30 | 2020-04-14 | 广西医科大学 | Aptamer screening and identifying method of T cell immune checkpoint PD-L1 and anti-tumor application |
| CN115786349A (en) * | 2022-08-16 | 2023-03-14 | 湖南大学 | Aptamer for traceless sorting of killer T lymphocytes in peripheral blood, complementary sequence and application of aptamer |
| CN115786350A (en) * | 2022-08-16 | 2023-03-14 | 湖南大学 | Aptamer capable of specifically recognizing and combining peripheral blood T lymphocytes, complementary sequence and application of aptamer and complementary sequence |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111004805A (en) * | 2019-12-30 | 2020-04-14 | 广西医科大学 | Aptamer screening and identifying method of T cell immune checkpoint PD-L1 and anti-tumor application |
| CN115786349A (en) * | 2022-08-16 | 2023-03-14 | 湖南大学 | Aptamer for traceless sorting of killer T lymphocytes in peripheral blood, complementary sequence and application of aptamer |
| CN115786350A (en) * | 2022-08-16 | 2023-03-14 | 湖南大学 | Aptamer capable of specifically recognizing and combining peripheral blood T lymphocytes, complementary sequence and application of aptamer and complementary sequence |
| CN115786350B (en) * | 2022-08-16 | 2023-08-25 | 湖南大学 | Aptamer capable of specifically recognizing and combining peripheral blood T lymphocytes, complementary sequence and application thereof |
| CN115786349B (en) * | 2022-08-16 | 2024-02-09 | 湖南大学 | Aptamer for traceless sorting of killer T lymphocytes in peripheral blood, complementary sequence and application of aptamer |
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