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Biomedical subjects

Yasunobu Yoshikai

Publications and source records attributed to Yasunobu Yoshikai.

At least 19 recordsLinked to original sources
PubMed2007

Enforced expression of Bcl-2 partially restores cell numbers but not functions of TCRgammadelta intestinal intraepithelial T lymphocytes in IL-15-deficient mice.

IL-15 knockout (KO) mice have severely reduced numbers of TCRgammadelta intestinal intraepithelial T lymphocytes (i-IEL), suggesting requirements of IL-15 signaling in the development or maintenance of i-IEL. To determine an involvement of survival signals via Bcl-2 in IL-15-mediated homeostasis of TCRgammadelta i-IEL, we introduced a bcl-2 transgene into IL-15 KO mice. In situ apoptosis of TCRgammadelta i-IEL was decreased in Bcl-2 transgenic (Tg) x IL-15 KO mice compared with IL-15 KO mice. The enforced expression of Bcl-2 partially restored the numbers of TCRgammadelta i-IEL in IL-15 KO mice. However, effector functions of TCRgammadelta i-IEL, including cytokine production and cytotoxic activity, were not recovered in Bcl-2 Tg x IL-15 KO mice. Importantly, TCRgammadelta i-IEL in Bcl-2 Tg x IL-15 KO mice expressed a reduced level of eomesodermin, a transcription factor critical for effector functions of NK cells and CD8(+) T cells. Similar to the case of TCRgammadelta i-IEL, enforced expression of Bcl-2 restored the numbers but not the functions of NK cells in IL-15 KO mice. These results suggest that Bcl-2-mediated survival signal is involved in the IL-15-mediated homeostasis of TCRgammadelta i-IEL and NK cells, but other signals from IL-15 are critical for inducing transcription factors, such as eomesodermin for their effector functions.

Animals↗
PubMed2006

Regulatory roles of NKT cells in the induction and maintenance of cyclophosphamide-induced tolerance.

We have previously reported the sequential mechanisms of cyclophosphamide (CP)-induced tolerance. Permanent acceptance of donor skin graft is readily induced in the MHC-matched and minor Ag-mismatched recipients after treatment with donor spleen cells and CP. In the present study, we have elucidated the roles of NKT cells in CP-induced skin allograft tolerance. BALB/c AnNCrj (H-2(d), Lyt-1.2, and Mls-1(b)) wild-type (WT) mice or Valpha14 NKT knockout (KO) (BALB/c) mice were used as recipients, and DBA/2 NCrj (H-2(d), Lyt-1.1, and Mls-1(a)) mice were used as donors. Recipient mice were primed with 1 x 10(8) donor SC i.v. on day 0, followed by 200 mg/kg CP i.p. on day 2. Donor mixed chimerism and permanent acceptance of donor skin allografts were observed in the WT recipients. However, donor skin allografts were rejected in NKT KO recipient mice. In addition, the donor reactive Vbeta6(+) T cells were observed in the thymus of a NKT KO recipient. Reconstruction of NKT cells from WT mice restored the acceptance of donor skin allografts. In addition, donor grafts were partially accepted in the thymectomized NKT KO recipient mice. Furthermore, the tolerogen-specific suppressor cell was observed in thymectomized NKT KO recipient mice, suggesting the generation of regulatory T cells in the absence of NTK cells. Our results suggest that NKT cells are essential for CP-induced tolerance and may have a role in the establishment of mixed chimerism, resulting in clonal deletion of donor-reactive T cells in the recipient thymus.

Animals↗
PubMed2006

Critical roles of memory T cells and antidonor immunoglobulin in rejection of allogeneic bone marrow cells in sensitized recipient mice.

BACKGROUND: Allosensitization is a major risk factor for graft failure in clinical bone marrow transplantation, even with an human leukocyte antigen (HLA)-matched combination under radiation-based conditioning regimens. The critical components of immunological memory in donor bone marrow graft rejection in allosensitized hosts remain unclear at present. METHODS: C57BL/6-recipient mice, which had been intraperitoneally injected with splenocytes from donor C3H mice on day -35 (sensitized recipients), had been lethally irradiated with 10-Gy whole-body irradiation and were intravenously injected with T-cell-depleted bone marrow cells (TCD-BMC) from C3H mice or third-party SJL mice. RESULTS: Lethally irradiated recipient mice, which had been sensitized by donor splenocytes 5 weeks before the transplantation of TCD-BMC, completely rejected the donor-BMC in a donor-specific manner, whereas none of the nonsensitized recipient mice, all of which showed full allogeneic chimerism, rejected the donor TCD-BMC. Antibody-mediated T cell and/or Natural Killer (NK) cell depletion did not improve the ability of the sensitized recipients to overcome the rejection even when a megadose of TCD-BMC was administered to the sensitized recipients. Furthermore, BMC rejection occurred in sensitized B cell-deficient mice. In adoptive transfer experiments, naive mice, which received a transfer of purified T cells from sensitized mice, rejected the donor BMC, but not those from nonsensitized mice. Moreover, naive mice, which received a transfer of serum containing antidonor immunoglobulin, rejected the donor BMC. CONCLUSIONS: These findings suggest that alloreactive memory T cells and antidonor immunoglobulin independently function to reject donor BMC in sensitized recipients.

Adoptive Transfer↗
PubMed2006

MyD88-dependent signaling for IL-15 production plays an important role in maintenance of CD8 alpha alpha TCR alpha beta and TCR gamma delta intestinal intraepithelial lymphocytes.

Interaction between commensal bacteria and intestinal epithelial cells (i-ECs) via TLRs is important for intestinal homeostasis. In this study, we found that the numbers of CD8alphaalpha TCRalphabeta and TCRgammadelta intestinal intraepithelial lymphocytes (i-IELs) were significantly decreased in MyD88-deficient (-/-) mice. The expression of IL-15 by i-ECs was severely reduced in MyD88(-/-) mice. Introduction of IL-15 transgene into MyD88(-/-) mice (MyD88(-/-) IL-15 transgenic mice) partly restored the numbers of CD8alphaalpha TCRalphabeta and TCRgammadelta i-IELs. The i-IEL in irradiated wild-type (WT) mice transferred with MyD88(-/-) bone marrow (BM) cells had the same proportions of i-IEL as WT mice, whereas those in irradiated MyD88(-/-) mice transferred with WT BM cells showed significantly reduced proportions of CD8alphaalpha TCRalphabeta and TCRgammadelta i-IELs, as was similar to the proportions found in MyD88(-/-) mice. However, irradiated MyD88(-/-) IL-15 transgenic mice transferred with WT BM cells had increased numbers of CD8alphaalpha TCRalphabeta and TCRgammadelta subsets in the i-IEL. These results suggest that parenchymal cells such as i-ECs contribute to the maintenance of CD8alphaalpha TCRalphabeta and gammadelta i-IELs at least partly via MyD88-dependent IL-15 production.

Adaptor Proteins, Signal Transducing↗
PubMed2006

IL-15 prevents allergic rhinitis through reactivation of antigen-specific CD8+ cells.

BACKGROUND: Allergic rhinitis is one of the most common allergic inflammatory diseases characterized by a predominant TH2 response with antigen-specific IgE synthesis. IL-15 plays important roles in activation and maintenance of memory CD8+T cells capable of producing IFN-gamma, which regulates TH2 responses. OBJECTIVE: To investigate the roles of endogenous IL-15 in allergic inflammation, we examined allergic rhinitis in IL-15 knockout (KO) mice sensitized with ovalbumin followed by intranasal rechallenge with ovalbumin. METHODS: IL-15KO mice were sensitized intraperitoneally with ovalbumin/complete Freund's adjuvant on day 0 and ovalbumin/IFA on day 7, and then were intranasally challenged with ovalbumin on days 21, 22, 23, 24, and 25. Nasal symptoms and histologic changes were examined. IgE production and TH2 responses were measured by ELISA. Purified CD8+T cells or recombinant IL-15 were administered into ovalbumin-sensitized mice. RESULTS: The levels of IgE production and TH2 responses in IL-15KO mice were comparable to those in control mice after ovalbumin sensitization. However, sneezing, infiltration of eosinophils into the nasal mucosa, and TH2 cytokine production were aggravated in ovalbumin-sensitized IL-15KO mice after intranasal challenge with ovalbumin. Adoptive transfer of CD8+6 T cells from ovalbumin-sensitized mice suppressed the TH2 responses in mice but not in IL-15KO mice. Administration of IL-15 with ovalbumin significantly prevented the development of allergic rhinitis in ovalbumin-sensitized mice. CONCLUSION: We demonstrate with IL-15KO mice that endogenous IL-15 plays an important role in suppression of allergic rhinitis at effector phase. Intranasal administration of IL-15 is useful as a therapeutic approach to control allergic rhinitis. CLINICAL IMPLICATIONS: Intranasal administration of recombinant IL-15 might become new immunotherapy for allergic rhinitis.

Administration, Intranasal↗
PubMed2006

Impaired protection against Mycobacterium bovis bacillus Calmette-Guerin infection in IL-15-deficient mice.

To investigate the potential role of endogenous IL-15 in mycobacterial infection, we examined protective immunity in IL-15-deficient (IL-15(-/-)) mice after infection with Mycobacterium bovis bacillus Calmette-Guérin (BCG) or recombinant OVA-expressing BCG (rBCG-OVA). IL-15(-/-) mice exhibited an impaired protection in the lung on day 120 after BCG infection as assessed by bacterial growth. CD4(+) Th1 response capable of producing IFN-gamma was normally detected in spleen and lung of IL-15(-/-) mice on day 120 after infection. Although Ag-specific CD8 responses capable of producing IFN-gamma and exhibiting cytotoxic activity were detected in the lung on day 21 after infection with rBCG-OVA, the responses were severely impaired on days 70 and 120 in IL-15(-/-) mice. The degree of proliferation of Ag-specific CD8(+) T cells in IL-15(-/-) mice was similar to that in wild-type mice during the course of infection with rBCG-OVA, whereas sensitivity to apoptosis of Ag-specific CD8(+) T cells significantly increased in IL-15(-/-) mice. These results suggest that IL-15 plays an important role in the development of long-lasting protective immunity to BCG infection via sustaining CD8 responses in the lung.

Animals↗
PubMed2006

IL-15 regulates CD8+ T cell contraction during primary infection.

During the course of acute infection with an intracellular pathogen, Ag-specific T cells proliferate in the expansion phase, and then most of the T cells die by apoptosis in the following contraction phase, but the few that survive become memory cells and persist for a long period of time. Although IL-15 is known to play an important role in long-term maintenance of memory CD8+ T cells, the potential roles of IL-15 in CD8+ T cell contraction are not known. Using an adoptive transfer system of OT-I cells expressing OVA257-264/Kb-specific TCR into control, IL-15 knockout (KO) and IL-15 transgenic (Tg) mice followed by challenge with recombinant Listeria monocytogenes expressing OVA, we found that the survival of CD44+CD62L-CD127- effector OT-I cells during the contraction phase is critically dependent on IL-15. In correlation with the expression level of Bcl-2 in OT-I cells, the number of OT-I cells was markedly reduced in IL-15 KO mice but remained at a high level in IL-15 Tg mice during the contraction phase, compared with control mice. In vivo administration of rIL-15 during the contraction phase in IL-15 KO mice inhibited the contraction of effector OT-I cells accompanied by up-regulation of Bcl-2 expression. Furthermore, enforced expression of Bcl-2 protected the majority of effector OT-I cells from death in IL-15 KO mice after infection. These results suggest that IL-15 plays a critical role in protecting effector CD8+ T cells from apoptosis during the contraction phase following a microbial infection via inducing antiapoptotic molecules.

Adoptive Transfer↗
PubMed2006

An important role of Tyk2 in APC function of dendritic cells for priming CD8+ T cells producing IFN-gamma.

Tyrosine kinase 2 (Tyk2) contributes to the signals triggered by IL-12 for IFN-gamma production by NK cells and T cells. We found in this study that Tyk2-deficient (-/-) mice showed increased susceptibility at the early stage after an i.p. infection with Listeria monocytogenes, accompanied by impaired IFN-gamma production. The numbers of both MHC class Ib (H2-M3)- or MHC class Ia (Kb)-restricted CD8+ T cells producing IFN-gamma and exhibiting cytotoxicity were significantly decreased in Tyk2-/- mice after infection with L. monocytogenes. Using an adoptive transfer system of OT-I cells expressing OVA(257-264)/Kb-specific TCR into Tyk2-/- mice followed by challenge with recombinant L. monocytogenes expressing OVA, we found that the defective Tyk2 signaling in the host environment was at least partially responsible for the impaired CD8+ T cytotoxic-1 (Tc1) cell responses in Tyk2-/- mice following the infection. Adoptive transfer with MHC class Ib- or MHC class Ia-binding peptide-pulsed BM-derived DC from Tyk2-/- mice induced lower levels of the Ag-specific CD8+ Tc1 cells producing IFN-gamma. These results suggest that Tyk2 signaling is also important for DC function in the induction of MHC class Ia- and class Ib-restricted CD8+ Tc1 cells following L. monocytogenes infection.

Adoptive Transfer↗
PubMed2006

Daily intake of heat-killed Lactobacillus plantarum L-137 augments acquired immunity in healthy adults.

Heat-killed Lactobacillus plantarum strain L-137 (HK-LP) is a potent inducer of IL-12 in vitro as well as in vivo in mice. HK-LP has been shown to suppress IgE production against food allergens, as well as tumor growth in mice, through IL-12 production, which induces the T helper (Th) 1 type immune response. To determine whether the intake of HK-LP influences immune function and the quality of life (QOL), a randomized, double-blind, placebo-controlled, parallel study was conducted in healthy subjects. Sixty subjects (30 men and 30 women, mean age 56.3 y) were randomly assigned to receive a capsule containing 10 mg of HK-LP daily or a matching capsule for 12 wk. Biomarkers for innate immunity such as the natural killer activity of peripheral blood mononuclear cells, neutrophil phagocytosis, and cell surface expression of CD64 on monocytes were measured every 4 wk. Biomarkers for acquired immunity such as concanavalin A (Con A)-induced proliferation, percentages of INF-gamma and IL-4-producing cluster of differentiation (CD)4(+) T cells (Th1:Th2 ratio), and the serum IgG4:IgG ratio were measured every 4 wk or at wk 0 and wk 12. Health-related QOL was assessed using a self-rating questionnaire with 26 items. Among the measured biomarkers, the percent change in Con A-induced proliferation and the Th1:Th2 ratio in the HK-LP group was greater than those in the control group (P = 0.036 and P = 0.002, respectively). The degree of improvement in QOL was higher in the HK-LP group than in the control group at wk 8 (P = 0.049) and tended to be higher at wk 12 (P = 0.092). These results suggest that a daily intake of HK-LP augments acquired immunity, especially Th1-related immune functions in healthy subjects, thereby improving the health-related QOL.

Adult↗
PubMed2006

[Crosstalk between innate and adaptive immunity].

Most of microorganisms are detected and destroyed within hours by innate immunity which does not generate lasting protective immunity. Innate immunity is mainly mediated by macrophages, dendritic cells and NK cells. Adaptive response is mediated by antigen-specific lymphocytes, which generate specific immunological memory, providing long-lasting protection. Th1 cells produce interferon (IFN)-gamma which mediate cell-mediate immunity, while Th2 cells help B cell to produce antibody via IL-4, 5, 6 production. Tr cells producing IL-10 are responsible for termination of excessive immune inflammations. IFN are divided into two main classes: type I IFN such as IFN-alpha, beta and type II IFN (IFN -gamma), both of which serve not only to bridge the gap between innate and adaptive immunity but also to shape subsequent development of adaptive immunity.

Animals↗
PubMed2005

Renal cancer treatment with low levels of mixed chimerism induced by nonmyeloablative regimen using cyclophosphamide in mice.

Recently, much attention has been paid to nonmyeloablative allogeneic stem cell transplantation for the treatment of metastatic renal cancer. Mature donor T cells cause graft-versus-host disease (GVHD) although they are also the main mediators of the beneficial graft-versus-tumor activity associated with this treatment. Hence, the segregation of the graft-versus-tumor activity from GVHD is an important challenge in managing the clinical course of treatment. We previously reported a series of studies regarding the allograft tolerance induced by allogeneic spleen cells (with bone marrow cells) and cyclophosphamide in mice. Here, we show a modified cyclophosphamide-induced tolerance system for the treatment of murine renal cell carcinoma, RENCA, by shifting the equal balance between graft-versus-host and host-versus-graft reactions toward graft-versus-host reaction with donor lymphocyte infusion. Our results clearly show the antitumor activity against RENCA with only low levels of mixed chimerism in the periphery and the in vivo and in vitro acquired immunity against RENCA even when mixed chimerism is almost undetectable. Because the withdrawal of mixed chimerism reduces the risk of GVHD, the antitumor activity is thus sequentially segregated from the initial GVHD in our model. We believe that this is the first unique model system of nonmyeloablative allogeneic hemopoietic cell transplantation to ever be reported for the treatment of renal cancer.

Animals↗
PubMed2005

A novel role of CD30/CD30 ligand signaling in the generation of long-lived memory CD8+ T cells.

Memory CD8+ T cells can be divided into two subsets, central memory (T(CM)) and effector memory (T(EM)) CD8+ T cells. We found that CD30, a member of the TNFR-associated factor (TRAF)-linked TNFR superfamily, signaling is involved in differentiation of long-lived CD8+ T(CM) cells following Listeria monocytogenes infection. Although CD8+ T(EM) cells transiently accumulated in the nonlymphoid tissues of CD30 ligand (CD153-/-) mice after infection, long-lived memory CD8+ T(CM) cells were poorly generated in these mice. CCR7 mRNA expression was down-regulated in CD8+ T cells of the spleen of CD153-/- mice in vivo and the expression was up-regulated in CD8+ T(EM) cells by anti-CD30 mAb cross-linking in vitro. These results suggest that CD30/CD30 ligand signaling plays an important role in the generation of long-lived memory CD8+ T cells at least partly by triggering homing receptors for T(CM) cells.

Animals↗
PubMed2005

Soluble branched (1,4)-beta-D-glucans from Acetobacter species enhance antitumor activities against MHC class I-negative and -positive malignant melanoma through augmented NK activity and cytotoxic T-cell response.

We previously found that an extracellular polysaccharide, AC-1, produced by Acetobacter polysaccharogenes composed of (1,4)-beta-D-glucan with branches of glucosyl residues showed a strong activity to induce production of interleukin (IL)-12 p40 and tumor necrosis factor-alpha by macrophage cell lines in vitro via Toll-like receptor-4 signaling. In the present study, we examined the effects of oral administration of AC-1 on protection against 2 types of murine B16 melanoma lines, major histocompatibility complex (MHC) class I-negative B16L and MHC class I gene-transfected B16K(b) cells. Mice were inoculated subcutaneously with B16L or B16K(b) cells on day 0 and administrated intragastrically with AC-1 or PBS once every 5 days from 1 day before tumor inoculation. The tumor growth was severely retarded in AC-1-treated mice after subcutaneous inoculation with B16L or B16K(b) cells. The AC-1-treated mice showed augmented natural killer (NK) cell activity against B16L cells, and in vivo depletion of NK cells by antiasialoGM1 antibody (Ab) treatment abrogated the antitumor activity in AC-1-treated mice. On the other hand, AC-1-treated mice inoculated with B16K(b) cells developed a significantly higher level of cytotoxic T-lymphocyte response against B16K(b) cells, and in vivo depletion of CD8(+) T cells by anti-CD8 mAb treatment abrogated the antitumor activity. Thus, AC-1 augmented antitumor activity against different tumors via augmentation of different antitumor mechanisms. These results suggest a possible prophylactic application of AC-1 for human neoplasms irrespective of expression levels of their MHC class I molecules.

Acetobacter↗
PubMed2005

A novel role of IL-15 in early activation of memory CD8+ CTL after reinfection.

A rapid induction of effector functions in memory T cells provides rapid and intensified protection against reinfection. To determine potential roles of IL-15 in early expansion and activation of memory CD8+ T cells in secondary immune response, we examined the cell division and cytotoxicity of memory CD8+ T cells expressing OVA(257-264)/Kb-specific TCR that were transferred into IL-15-transgenic (Tg) mice, IL-15 knockout (KO) mice, or control C57BL/6 mice followed by challenge with recombinant Listeria monocytogenes expressing OVA (rLM-OVA). In vivo CTL activities and expression of granzyme B of the transferred CD8+ T cells were significantly higher in the IL-15 Tg mice but lower in the IL-15 KO mice than those in control mice at the early stage after challenge with rLM-OVA. In contrast, there was no difference in the cell division in IL-15 Tg mice and IL-15 KO mice compared with those in control mice. In vivo administration of rIL-15 conferred robust protection against reinfection via induction of granzyme B in the memory CD8+ T cells. These results suggest that IL-15 plays an important role in early activation of memory CD8+ T cells.

Adoptive Transfer↗
PubMed2005

Oral administration of bovine colostrum stimulates intestinal intraepithelial lymphocytes to polarize Th1-type in mice.

Th1 stimulus for Th2-skewed immune response during infancy is important for reduction of incidence of allergic diseases. We examined effects of oral administration of bovine colostrum on local immunity in intestine in adult mice. C57BL/6 mice were orally given bovine colostrum or control milk for 1, 3 or 6 months and intestinal microflora, fecal IgA, and lymphocyte population of gut-associated lymphoid tissues and their abilities of cytokine production were examined. Although the cell populations of intestinal intraepithelial lymphocytes (i-IEL) were not remarkably changed, the T cells in i-IEL were polarized to Th1 type after oral administration of bovine colostrum. Intestinal microflora and IgA levels in feces were not changed by oral administration of bovine colostrum. These results suggest that colostrum stimulates directly to i-IEL to polarize Th1 type, which may protect from infectious diseases and allergic diseases mediated by Th2 type responses.

Administration, Oral↗
PubMed2005

Isomalto-oligosaccharides polarize Th1-like responses in intestinal and systemic immunity in mice.

Isomalto-oligosaccharides (IMO) belong to a group of prebiotics that significantly increase the number of protective gut microflora. In the present study, we investigated the effects of IMO on intestinal and systemic immunity in mice. When mice were fed a diet supplemented with 20% IMO for 4 wk, the number of lactobacilli and the levels of IgA in feces were greater than those of mice fed the control diet (P < 0.05). Interferon-gamma (IFN-gamma) production by intestinal intraepithelial lymphocytes (i-IEL) in response to T-cell receptor (TCR) triggering was greater in mice fed IMO than in controls (P < 0.05), indicating T helper-1 (Th1) polarization of intestinal immunity by IMO. The proportion of natural killer (NK) T cells in the liver mononuclear cells (MNC), and the production of IFN-gamma by the liver MNC in response to TCR triggering were greater in mice fed IMO than in controls (P < 0.05), suggesting that the Th1/Th2 balance was shifted toward the Th1 lineage by IMO in systemic immunity. Furthermore, the proportion and activity of NK cells were greater in the spleens of the mice fed IMO than in the controls. Dietary IMO protected the mice from gamma-irradiation-induced lethality, accompanied by an inhibition of the translocation of Enterobacteriaceae. Notably, when mouse macrophage-like J774.1 cells were cultured with Lactobacillus gasseri in the presence of IMO, interleukin (IL)-12 production was greater than in the absence of IMO. These results suggest that IMO, in synergy with lactobacilli, upregulate the Th1 response and beneficially modulate host defense.

Animals↗
PubMed2005

A novel autoregulatory mechanism for transcriptional activation of the IL-15 gene by a nonsecretable isoform of IL-15 generated by alternative splicing.

There are several isoforms of interleukin (IL) -15 generated by alternating splicing. We reported previously that alternative IL-15 transgenic (Tg) mice expressing an IL-15 cDNA isoform encoding nonsecretable IL-15 protein had an impaired ability to produce IL-15. In this study, we found that expression of endogenous IL-15 mRNA but not tumor necrosis factor alpha mRNA was severely impaired in response to lipopolysaccharide, not only in macrophages from alternative IL-15 Tg mice but also in RAW264.7 cells that had been transfected with alternative IL-15 together with IL-15 receptor alpha (IL-15Ralpha). IL-15 promoter activity was suppressed in the transfected cells. Although nuclear factor-kappaB activation was not impaired, the binding activity of nuclear extracts to the interferon-stimulated response element of the IL-15 promoter region was reduced in RAW264.7 cells, which had been cotransfected with alternative IL-15 and IL-15Ralpha. IL-15 was mainly colocalized with IL-15Ralpha at the cytoplasmic membrane of RAW264.7 cells, which had been cotransfected with normal IL-15, whereas nonsecretable IL-15 was colocalized with IL-15Ralpha in nucleus after cotransfection with alternative IL-15 and IL-15Ralpha. These results suggest that nonsecretable IL-15 generated by alternative splicing suppresses further IL-15 gene transcription, implying a novel autocrine regulatory mechanism for cytokine gene expression by alternative splicing.

Alternative Splicing↗