Abstract
CD4 T cells play a cardinal role in orchestrating immune system. Differentiation of CD4 T cells to Th1 and Th2 effector subsets depends on multiple factors such as relative intensity of interactions between T cell receptor with peptide-major histocompatibility complex, cytokine milieu, antigen dose, and costimulatory molecules. Literature supports the critical role of peptide’s binding affinity to Human Leukocyte Antigens (HLAs) and in the differentiation of naïve CD4 T cells to Th1 and Th2 subsets. However, there exists no definite report addressing very precisely the correlation between physicochemical properties (hydrophobicity, hydrophilicity), pattern, position of amino acids in peptide and their role in skewing immune response towards Th1 and Th2 cells. This may play a significant role in designing peptide vaccines. Hence in the present study, we have evaluated the relationship between amino acid pattern and their influence in differentiation of Th1 and Th2 cells. We have used a data set of 320 peptides, whose role has been already established experimentally in the generation of either Th1 or Th2 immune response. Further, characterization was done based on binding affinity, promiscuity, amino acid pattern and binding conformation of peptides. We have observed that distinct amino acids in peptides elicit either Th1 or Th2 immunity. Consequently, this study signifies that alteration in the sequence and type of selected amino acids in the HLA class II binding peptides can modulate the differentiation of Th1 and Th2 cells. Therefore, this study may have an important implication in providing a platform for designing peptide-based vaccine candidates that can trigger desired Th1 or Th2 response.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- HLA:
-
Human leukocyte antigen
- MSA:
-
Multiple sequence alignment
- pTh1 and pTh2:
-
Peptides eliciting Th1 and Th2 immune response, respectively
References
ACCELRYS SOFTWARE INC (2007) Discovery studio modeling environment, Release 2.5. Accelrys Software Inc, San Diego
Agrewala JN, Wilkinson RJ (1998) Differential regulation of Th1 and Th2 cells by p91–110 and p21–40 peptides of the 16-kD alpha-crystallin antigen of Mycobacterium tuberculosis. Clin Exp Immunol 114:392–397
Arnold PY, la Gruta NL, Miller T, Vignali KM, Adams PS, Woodland DL, Vignali DA (2002) The majority of immunogenic epitopes generate CD4+T cells that are dependent on MHC class II-bound peptide-flanking residues. J Immunol 169:739–749
Badou A, Savignac M, Moreau M, Leclerc C, Foucras G, Cassar G, Paulet P, Lagrange D, Druet P, Guery JC, Pelletier L (2001) Weak TCR stimulation induces a calcium signal that triggers IL-4 synthesis, stronger TCR stimulation induces MAP kinases that control IFN-γ production. Eur J Immunol 31:2487–2496
Basu R, Bhaumik S, Basu JM, Naskar K, De T, Roy S (2005) Kinetoplastid membrane protein-11 DNA vaccination induces complete protection against both pentavalent antimonial-sensitive and-resistant strains of Leishmania donovani that correlates with inducible nitric oxide synthase activity and IL-4 generation: evidence for mixed Th1- and Th2-like responses in visceral leishmaniasis. J Immunol 174:7160–7171
Black M, Trent A, Tirrell M, Olive C (2010) Advances in the design and delivery of peptide subunit vaccines with a focus on toll-like receptor agonists. Expert Rev Vaccines 9:157–173
Blander JM, Sant’angelo DB, Bottomly K, Janeway CA Jr (2000) Alteration at a single amino acid residue in the T cell receptor alpha chain complementarity determining region 2 changes the differentiation of naive CD4 T cells in response to antigen from T helper cell type 1 (Th1) to Th2. J Exp Med 191:2065–2074
Boyton RJ, Altmann DM (2002) Is selection for TCR affinity a factor in cytokine polarization? Tren Immunol 23:526–529
Brusic V, Bajic VB, Petrovsky N (2004) Computational methods for prediction of T-cell epitopes-a framework for modelling, testing, and applications. Methods 34:436–443
Constant SL, Bottomly K (1997) Induction of Th1 and Th2 CD4+T cell responses: the alternative approaches. Annu Rev Immunol 15:297–322
de Montmollin E, Aboab J, Mansart A, Annane D (2009) Bench-to-bedside review: beta-adrenergic modulation in sepsis. Crit Care 13:230
DeLano WL (2002) The PyMOL molecular graphics system. DeLano Scientific, San Carlos. http://www.pymol.org
Donnes P, Elofsson A (2002) Prediction of MHC class I binding peptides, using SVMHC. BMC Bioinfo 3:25
Dubey C, Croft M, Swain SL (1995) Costimulatory requirements of naive CD4+T cells. ICAM-1 or B7-1 can costimulate naive CD4 T cell activation but both are required for optimum response. J Immunol 155:45–57
Gowthaman U, Agrewala JN (2008) In silico tools for predicting peptides binding to HLA-class II molecules: more confusion than conclusion. J Proteome Res 7:154–163
Guy B, Krell T, Sanchez V, Kennel A, Manin C, Sodoyer R (2005) Do Th1 or Th2 sequence motifs exist in proteins? Identification of amphipathic immunomodulatory domains in Helicobacter pylori catalase. Immunol Let 96:261–275
Hess B, Kutzner C, van der Spoel D, Lindahl E (2008) GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation. J Chem Theory Comp 4:435–447
Huey R, Morris GM, Olson AJ, Goodsell DS (2007) A semiempirical free energy force field with charge-based desolvation. J Comput Chem 28:1145–1152
Iezzi G, Scotet E, Scheidegger D, Lanzavecchia A (1999) The interplay between the duration of TCR and cytokine signaling determines T cell polarization. Eur J Immunol 29:4092–4101
Kumar V, Bhardwaj V, Soares L, Alexander J, Sette A, Sercarz E (1995) Major histocompatibility complex binding affinity of an antigenic determinant is crucial for the differential secretion of interleukin 4/5 or interferon gamma by T cells. Proc Natl Acad Sci USA 92:9510–9514
Lafuente EM, Reche PA (2009) Prediction of MHC–peptide binding: a systematic and comprehensive overview. Curr Pharm Des 15:3209–3220
Larkin MA, Blackshields G, Brown NP, Chenna R, McGettigan PA, McWilliam H, Valentin F, Wallace IM, Wilm A, Lopez R, Thompson JD, Gibson TJ, Higgins DG (2007) Clustal W and Clustal X version 2.0. Bioinformatics 23:2947–2948
Liao WW, Arthur JW (2011) Predicting peptide binding to major histocompatibility complex molecules. Autoimmun Rev 10:469–473
Liew FY, Millott SM, Schmidt JA (1990) A repetitive peptide of Leishmania can activate T helper type 2 cells and enhance disease progression. J Exp Med 172:1359–1365
Milich DR, Peterson DL, Schodel F, Jones JE, Hughes JL (1995) Preferential recognition of hepatitis B nucleocapsid antigens by Th1 or Th2 cells is epitope and major histocompatibility complex dependent. J Virol 69:2776–2785
Mosmann TR, Coffman RL (1989) TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 7:145–173
Murray JS (1998) How the MHC selects Th1/Th2 immunity. Immunol Today 19:157–163
Nakajima-Adachi H, Koike E, Totsuka M, Hiraide E, Wakatsuki Y, Kiyono H, Hachimura S (2012) Two distinct epitopes on the ovalbumin 323–339 peptide differentiating CD4+t cells into the Th2 or Th1 phenotype. Biosci Biotechnol Biochem 76(10):1979–1981
Nielsen M, Lundegaard C, Lund O (2007) Prediction of MHC class II binding affinity using SMM-align, a novel stabilization matrix alignment method. BMC Bioinfo 8:238
North RJ, Jung YJ (2004) Immunity to tuberculosis. Annu Rev Immunol 22:599–623
O’Brien C, Flower DR, Feighery C (2008) Peptide length significantly influences in vitro affinity for MHC class II molecules. Immunome Res 4:6
Pereira BA, Silva FS, Rebello KM, Marin-Villa M, Traub-Cseko YM, Andrade TC, Bertho AL, Caffarena ER, Alves CR (2011) In silico predicted epitopes from the COOH–terminal extension of cysteine proteinase B inducing distinct immune responses during Leishmania (Leishmania) amazonensis experimental murine infection. BMC Immunol 12:44
Pfeiffer C, Stein J, Southwood S, Ketelaar H, Sette A, Bottomly K (1995) Altered peptide ligands can control CD4 T lymphocyte differentiation in vivo. J Exp Med 181:1569–1574
Pulendran B, Artis D (2012) New paradigms in type 2 immunity. Science 337:431–435
Purvis HA, Stoop JN, Mann J, Woods S, Kozijn AE, Hambleton S, Robinson JH, Isaacs JD, Anderson AE, Hilkens CM (2010) Low-strength T-cell activation promotes Th17 responses. Blood 116:4829–4837
Reiner SL, Locksley RM (1995) The regulation of immunity to Leishmania major. Annu Rev Immunol 13:151–177
Rothbard JB, Taylor WR (1988) A sequence pattern common to T cell epitopes. EMBO J 7:93–100
Sanner MF (1999) Python: a programming language for software integration and development. J Mol Graph Model 17:57–61
Singh H, Raghava GP (2001) ProPred: prediction of HLA-DR binding sites. Bioinformatics 17:1236–1237
Soloway P, Fish S, Passmore H, Gefter M, Coffee R, Manser T (1991) Regulation of the immune response to peptide antigens: differential induction of immediate-type hypersensitivity and T cell proliferation due to changes in either peptide structure or major histocompatibility complex haplotype. J Exp Med 174:847–858
Swain SL, Weinberg AD, English M, Huston G (1990) IL-4 directs the development of Th2-like helper effectors. J Immunol 145:3796–3806
Tongchusak S, Leelayuwat C, Brusic V, Chaiyaroj SC (2008) In silico prediction and immunological validation of common HLA-DRB1-restricted T cell epitopes of Candida albicans secretory aspartyl proteinase 2. Microbiol Immunol 52:231–242
Vita R, Zarebski L, Greenbaum JA, Emami H, Hoof I, Salimi N, Damle R, Sette A, Peters B (2010) The immune epitope database 2.0. Nucl Acids Res 38:D854–D862
Wang P, Sidney J, Dow C, Mothe B, Sette A, Peters B (2008) A systematic assessment of MHC class II peptide binding predictions and evaluation of a consensus approach. PLoS Comput Biol 4(4):e1000048
Waterhouse AM, Procter JB, Martin DM, Clamp M, Barton GJ (2009) Jalview Version 2––a multiple sequence alignment editor and analysis workbench. Bioinformatics 25:1189–1191
Whelan M, Harnett MM, Houston KM, Patel V, Harnett W, Rigley KP (2000) A filarial nematode-secreted product signals dendritic cells to acquire a phenotype that drives development of Th2 cells. J Immunol 164:6453–6460
Zhang R, Yoshida A, Kumagai T, Kawaguchi H, Maruyama H, Suzuki T, Itoh M, El-Malky M, Ohta N (2001) Vaccination with calpain induces a Th1-biased protective immune response against Schistosoma japonicum. Infect Immun 69:386–391
Zhang J, Jia Z, Lin Z, Li J, Fu X, Huang Y, Zhao J, Nie L, Hou W, Yuan F, Wu Y (2012) Computational prediction and experimental assessment of an HLA-A*0201-restricted cytotoxic T lymphocyte epitope from neutral endopeptidase. Immunol Res 52:231–239
Zhu J, Paul WE (2008) CD4 T cells: fates, functions, and faults. Blood 112:1557–1569
Acknowledgments
The authors are thankful to Dr. Balvinder Singh, CSIR-Institute of Microbial Technology, Chandigarh for valuable suggestions and Dr. Uthaman Gowthaman, Yale School of Medicine, New Haven, USA for peptide data collection. The authors also thank Council of Scientific and Industrial Research (CSIR), India for financial support. SBC, KM, PKR, SM, JAS are recipients of fellowship of CSIR, and MA of UGC.
Conflict of interest
The authors have no financial conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
726_2014_1692_MOESM1_ESM.tif
Frequency of Th1 and Th2 skewing HLA binder peptides. Th1 (A) and Th2 (B) inducing peptides were checked for their binding capability with predominantly occurring HLA alleles in human population by using ProPred and SVMHC methods. Solid and open bars indicate binders and non-binders, respectively. X-axis represents the selected HLA alleles and Y-axis implies to the number of peptides. (TIFF 1021 kb)
726_2014_1692_MOESM2_ESM.tif
Incidence of Th1 and Th2 evoking HLA binding promiscuous peptides. Bar diagrams depict the percentage of Th1 and Th2 generating promiscuous and non-promiscuous peptides (A); strong and weak affinity binding Th1 and Th2 inducing promiscuous peptides (B). X-axis represents the type of peptides and Y-axis percentage of promiscuity (A); binding affinity (B). (TIFF 23 kb)
726_2014_1692_MOESM3_ESM.tif
Binding improves with increasing length of peptide. Solid and open bar diagrams illustrate strong and weak affinity of HLA-II binders, which activate Th1 (A) and Th2 (B) cells, respectively. X-axis represents the number of amino acids in each peptide, whereas Y-axis indicates the number of strong and weak binders. (TIFF 53 kb)
726_2014_1692_MOESM4_ESM.tif
Relationship between length of the peptide and its promiscuous nature. Solid and open bar diagrams depict promiscuous and non-promiscuous HLA-II binders that activate Th1 (A) and Th2 (B) cells, respectively. X-axis represents the number of amino acids in each peptide, whereas Y-axis indicates the number of promiscuous and non-promiscuous HLA-II peptide binders. (TIFF 51 kb)
726_2014_1692_MOESM5_ESM.tif
Conserved hydrophobicity of pTh1 and pTh2 observed with other MHC as well: Pie diagrams represent percentage of conserved hydrophobicity (black) and hydrophilicity (grey) at the indicated positions of peptide binding region that evoke Th1 (A); Th2 (B) response. Each bar graph represents percentage occurrence at the indicated position of binding region. X-axis represents the hydrophilicity in an increasing order and Y-axis denotes percentage of amino acid at the particular position. (TIFF 3850 kb)
726_2014_1692_MOESM6_ESM.tif
Distinct conformational binding of pTh1 and pTh2 and their consensus. Conformations of pTh1, pTh2 and their consensus sequence bound to HLA (A). The HLA molecule is shown in surface and peptides as stick representations. Arrow indicates binding groove of HLA. Peptide sequences of Fig. 3A are tabulated (B). (TIFF 19980 kb)
726_2014_1692_MOESM7_ESM.xlsx
List of total peptides used in the study: Excel file contains peptide sequences, source, organism and MHC restriction of used pTh1 and pTh2. (XLSX 63 kb)
Rights and permissions
About this article
Cite this article
Mushtaq, K., Chodisetti, S.B., Rai, P.K. et al. Decision-making critical amino acids: role in designing peptide vaccines for eliciting Th1 and Th2 immune response. Amino Acids 46, 1265–1274 (2014). https://doi.org/10.1007/s00726-014-1692-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00726-014-1692-4