Identification of core T cell network based on immunome interactome
© Teku et al.; licensee BioMed Central Ltd. 2014
Received: 5 July 2013
Accepted: 5 February 2014
Published: 15 February 2014
Data-driven studies on the dynamics of reconstructed protein-protein interaction (PPI) networks facilitate investigation and identification of proteins important for particular processes or diseases and reduces time and costs of experimental verification. Modeling the dynamics of very large PPI networks is computationally costly.
To circumvent this problem, we created a link-weighted human immunome interactome and performed filtering. We reconstructed the immunome interactome and weighed the links using jackknife gene expression correlation of integrated, time course gene expression data. Statistical significance of the links was computed using the Global Statistical Significance (GloSS) filtering algorithm. P-values from GloSS were computed for the integrated, time course gene expression data. We filtered the immunome interactome to identify core components of the T cell PPI network (TPPIN). The interconnectedness of the major pathways for T cell survival and response, including the T cell receptor, MAPK and JAK-STAT pathways, are maintained in the TPPIN network. The obtained TPPIN network is supported both by Gene Ontology term enrichment analysis along with study of essential genes enrichment.
By integrating gene expression data to the immunome interactome and using a weighted network filtering method, we identified the T cell PPI immune response network. This network reveals the most central and crucial network in T cells. The approach is general and applicable to any dataset that contains sufficient information.
Cellular interactomes often consist of large numbers of proteins with even larger numbers of connections between them. Typically in protein-protein interaction (PPI) network nodes represent proteins and the links represent relationships between them. This network representation enables the study and visualization of the reconstructed cellular systems.
Data-driven studies on the dynamics of reconstructed PPI networks facilitate investigation and identification of proteins important for a particular process and reduces time and costs of experimental verification [1, 2]. Modeling the dynamics of very large PPI networks is computationally very costly. To circumvent this problem, one needs to identify relevant core components of networks without losing vital information. A PPI network constituting most of the relevant core of a cellular system is sufficient to study its dynamic properties .
Many methods have been developed to reduce complex directed and undirected networks to their core components. Some of the methods include topological centrality techniques , synthetic biology approaches of the minimal gene set of a cell [5, 6], complex systems coarse-graining [7, 8], and filtering approaches [9–11]. In the centrality methods, topological centrality of nodes is used to identify the non-redundant links and to delete the redundant ones . Minimal gene set approaches aim to identify genes that are crucial for life sustenance and cannot be inactivated under specific optimal growth conditions. These approaches do not take into account interactions between essential gene products . The coarse-graining approaches identify specific motifs in a network, and collapse and replace them by a single node . This process is repeated until there are no more motifs. The final network is less complex but does not consider the structural heterogeneity and broad weight distribution, i.e. the multi-scale nature, of cellular networks.
Network filtering approaches have also been used to reduce network complexity [10–13]. Those that preserve the inherent multiscale structure of natural complex networks have been shown to be better in revealing most of the important components of networks [11, 13]. These approaches score the nodes or links, and enable the deletion of those that do not deviate significantly from a null model.
In this study, we identified the network of proteins relevant in T cells by filtering the immunome interactome using the result from Global Statistical Significance (GloSS)  algorithm and a constraint of connectivity of the T cell receptor (TCR) signaling pathway. We compiled genes for the major immune processes and used them to reconstruct the immunome interactome, i.e., all the PPIs of the immunome. We then integrated gene expression profiles for the corresponding genes across several experiments. Jackknife correlation for gene expression was then used to weigh links between the proteins encoded by the genes. To maintain the multiscale structure of the network during filtering, we used the GloSS algorithm. This algorithm utilizes a global null model of the link weight and the degree distribution of the network. It computes the statistical significance for each link. For the null model, GloSS assigns weights from the weight distribution of the network, independently and randomly, without changing its topology. We filtered the network by deleting links based on their p-values (computed by GloSS) in descending order. To determine the endpoint of the filtering, we imposed as a constraint, the existence of a single path between the components of the NF-κB and TCR complexes.
Because we investigated the global and aggregate characteristics of the system and integrated T cell gene expressions, we can assume that the filtered network contains most of the components central for T cell signaling . This was supported by Gene Ontology (GO) and essential genes enrichment analysis.
Protein-protein interaction network
KEGG pathways used to supplement IKB dataset
Name of KEGG pathway
MAPK signaling pathway
Chemokine signaling pathway
Cell adhesion molecules
Antigen processing and presentation
Toll-like receptor signaling pathway
NOD-like receptor signaling pathway
RIG-1-like receptor signaling pathway
Jak-STAT signaling pathway
Hematopoietic cell lineage
Natural killer cell mediated cytotoxicity
T cell receptor signaling pathway
B cell receptor signaling pathway
FcϵRI signaling pathway
Leukocyte trans-endothelial migration
Intestinal immune network for IgA production
Complement and coagulation cascades
Cytosolic DNA-sensing pathway
Gene expression correlation
Next, the mean of the jackknife Pearson product-moment correlation coefficient was calculated for the pre-processed and merged expression values for all gene pair combinations. In total, 1140 genes representing 5164 gene pairs encoding interacting proteins in the immunome interactome were used for further analysis.
T cell-specific PPI network
We reconstructed the immunome PPI network as a weighted and undirected graph. The nodes, links, and link weights of the graph represent, respectively, the immunome protein coding genes, the PPIs and the absolute value of the mean jackknife expression correlation between the connected immunome protein coding genes.
The topology and weight distribution of naturally occurring complex weighted networks are heterogeneous and tightly connected. This makes the identification of the relevant structure that maintains the multiscale nature of the network nontrivial. Thus, we used the GloSS algorithm  to compute a p-value, for each link. GloSS identifies the relevant backbone of a weighted graph while retaining the multiscale coupling of its weight distribution and topological characteristics. It uses a global null model that describes both the structure of the network and its weight distribution. The p-values computed by GloSS were used to filter the network by deleting links based on their p-values, in descending order. We monitored the filtering process to make sure that the central networks between TCR, and NF-κB and NFAT signaling pathways remained intact. These pathways have been shown to be crucial for T cell signaling [26, 27] and therefore cannot be disconnected without destroying essential cellular processes.
General structure of the T cell PPI network
Number of nodes in connected component
Number of links
Number of components in the network
Correlation distribution before and after filtering
Effect of noise on the filtering procedure
To test the sensitivity of our filtering procedure to noise we introduced randomness to the immunome interactome, before performing filtering, by randomizing fractions of the link weights while preserving the topology of the network. We refer to these networks as the Link Weight-Randomized Networks (LWRNs). Nine such networks were created based on the fraction of weights randomized. Thirty iterations were conducted for each LWRN. Each iteration consists of choosing randomly a fraction of links, reassigning their weights randomly, conducting the filtering procedure, and calculating network topology statistics. The topology features calculated for each iteration include node degree, average path length, betweenness centrality of both the nodes and the links, clustering coefficient of the network, and the intersection between the TPPIN and the LWRN. These measures indicate the local and global connectivity of a network. We retained the average of the above quantities.
Gene Ontology over-representation and semantic similarity analysis
GO biological process term enrichment for TPPIN
Number of significant vs. annotated genes
Expected number of genes
Raw vs. adjusted P value
positive regulation of lymphocyte activation
5.40 × 10-09/9.74 × 10-07
regulation of programmed cell death
4.77 × 10-10/4.60 × 10-07
regulation of immune response
6.79 × 10-09/1.11 × 10-06
negative regulation of cellular process
1.05 × 10-08/1.62 × 10-06
positive regulation of cell activation
7.04 × 10-08/5.59 × 10-06
positive regulation of response to stimulus
5.10 × 10-08/4.40 × 10-06
regulation of apoptotic process
4.04 × 10-10/4.60 × 10-07
intracellular protein kinase cascade
3.13 × 10-08/3.40 × 10-06
Cytokine mediated signaling pathway
3.85 × 10-09/8.07 × 10-07
3.63 × 10-08/3.51 × 10-06
To better investigate the similarity or difference between the immunome interactome and the TPPIN network, we explored semantic similarity of the networks using the GOSemSim package available from R/Bioconductor. The semantic similarity ranges between 0 and 1. The similarity between the immunome interactome and TPPIN proteins in the biological process and molecular function terms were very high, i.e., 0.91 and 0.92, respectively, indicating that the TPPIN is very representative of the immunome interactome.
Essential genes over-representation analysis
Essential genes overrepresentation
Number of genes
Number of genes annotated in MGI
Number of lethality genes annotated in MGIa
Expected number of lethality genes in MGI
P-value for hypergeometric test
1.37 × 10-10
Interconnection of T cell-specific pathways
Discussion and conclusions
In this study, we identified the network of proteins relevant for T cells by filtering the multiscale immunome interactome using the GloSS filtering algorithm . We compiled the genes for the major immune processes and reconstructed the immunome interactome. Then we integrated gene expression profiles across several gene expression experiments. The jackknife correlation for gene expression was used to weigh links between the proteins encoded by the genes. Next, we used the output from GloSS to filter the network. The filtered network contains most of the relevant T cell functional components and was designated TPPIN. This was confirmed by the overrepresentation analysis conducted with GO terms and essential genes.
Many important components of the TCR-dependent signaling pathways are present in the TPPIN. Except for CD3γ and CD3δ, other components of the TCR complex which are included in the microarrays used in this study, are present (TCR-α and -β are not present in the microarrays). The co-receptors CD4 and CD8 are both present, as well as, all the proteins that make up the immunological synapse. With the exception of LAT, GADS and ITK, most proteins that are central in the immediate TCR receptor-associated intracellular signaling after the formation of the immunological synapse and TCR activation are present in the TPPIN, including LCK, FYN, CD45, ZAP70, SLP-76 and PLC-γ.
After its activation, PLC-γ cleaves PIP2 into the second messenger IP3 and DAG [31, 32]. This event sets off the activation of three important signaling pathways in T cells that end up with transcriptional activation of NFAT, NF-κB and AP-1 . DAG activates PKC-θ, which in turn activates NF-κB . IP3 activates CaN through the calcium signaling, and CaN subsequently activates NFAT . DAG activates RasGRP [35, 36], which in turn initiates the activation of the MAP kinase cascade , culminating in the activation of FOS . Key proteins in the NF-κB pathway including PKC-θ, IKK-β and IκB  are present in the TPPIN. With the exception of RasGRP, MEK1/2 and ELK co-complexes, the other vital proteins in the MAP kinase signaling cascade  and the JAK-STAT pathway  are captured by the TPPIN. These results show how the TPPIN represents relevant T cell-related parts of the immunome interactome.
During the filtering step the central networks connecting the TCR complex to the NF-κB and NFAT signaling pathways were kept intact. Although the NFAT and NF-κB pathways are present in many different cell-types, they are central for T cell survival and functions. The connectivity of these components was used to determine the end point for the filtering process. The filtering was continued until there was a minimum number of links, i.e., one, between the TCR, and NF-κB and NFAT components.
GO term enrichment analysis confirms that several of the TPPIN proteins have important T cell functions. As an example of biological process term enrichment, the positive regulation of lymphocyte activation pathway (GO:0051251), regulation of immune response (GO:0050776), and intracellular protein kinase cascade (GO:0007243) terms are significantly enriched. To further probe the similarity between the immunome interactome and the TPPIN proteins we calculated their semantic similarity with respect to biological process and molecular function GO terms. The networks were semantically very similar in both types of GO terms. Because essential genes are indispensable for the survival of a cell, their enrichment in the cellular network would indicate that the network is crucial to the cell. Thus, we investigated the enrichment of essential genes in the TPPIN. The analysis showed a highly significant enrichment of essential genes in the TPPIN. These independent lines of evidence support the applicability of the network filtering routine.
Due to the scarcity of time course microarray experiments with uniform design, gene expression datasets with different designs were used. Integrated analysis was carried out to identify and exclude biased datasets [42, 43]. The normalization and batch effect analysis steps served to considerably minimize the effect of bias for correlation calculation from the experimental studies.
Global and aggregate cellular interactions are more plausible between proteins encoded by co-expressed genes than between gene products whose expression patterns are uncorrelated . Since we investigated the global and aggregated characteristics of the immune response in T cells by integrating gene expression experiments conducted for T cell lines, the correlation coefficients represent the aggregate strength of the T cell-specific relationship between the genes and their interacting protein products [14, 44].
To explore the changes in the network during the filtering process we investigated changes in the diameter, relative size of the largest component and the average size of the connected components of the network. These network measures have been shown to indicate the connectivity status of a network and its robustness against link removal or loss [28, 45]. The changes in network statistics during the filtering process showed that TPPIN maintains most of the integrity and connectivity of the immunome interactome.
Certain aspects of T cell function have been previously modeled [46–49]. Most of these studies are related to gene regulatory networks and modeling of small signaling networks involving transcription factors and their targets, selected to include genes or proteins well-known in the modeled system. In these studies, the typical number of genes or proteins is in a few tens, whereas we started with the entire immunome interactome of 1149 proteins and 5164 links, and ended up with a core network that contains 288 proteins and 227 links. The number of nodes and links in the TPPIN makes it amenable to tailored cellular systems modeling and experimental studies. Our approach is unsupervised and does not utilize any preconceptions, yet, it reveals the central proteins and their networks.
The filtering process carried out in this study has some potential limitations. It needs several time course expression datasets for the cell-type or tissue of interest and each experiment should consist of at least 3 samples. A set of proteins is needed to track the connectivity of the vital pathways and a stop criterion when key pathways are broken. However, these limitations are not of great practical importance in the present era of high throughput studies.
The reported filtering routine can capture the core cell-type-specific PPI network for any cell-type from time series gene expression datasets, and is not limited to well-known systems. The approach opens ways for modeling protein interaction networks of cellular systems, even when pathways are not previously well characterized.
Protein-protein interaction network reconstruction
Experimentally verified and consolidated PPI data for the human immunome proteins was retrieved from the iRefIndex database version 9.0 . First, the ppiTrim version 1.2.1  was used to filter the iRefIndex dataset. This algorithm maps protein interactants to NCBI gene identifiers and removes undesired raw interactions, deflates potentially expanded complexes, and reconciles annotation labels from the different PPI databases. Second, non-experimentally verified, non-human, complex and self-self PPIs were omitted. Third, we collapsed multiple binary PPIs whose interactants are products of the same genes. Finally, we eliminated PPIs for which both interactants were not immunome proteins (Figure 1). The igraph library  in the R statistical programming environment  was used to reconstruct and analyze the PPI network. Visualizations were done using Cytoscape version 2.8 .
Gene expression data
We retrieved microarray time course datasets for human T cell-lines from GEO  and ArrayExpress  databases. Each experiment had to contain at least three samples and at least one for time zero for baseline data. GEO datasets that consisted of samples from multiple platforms were split into multiple experiments, so that each experiment consisted of samples for the same microarray platform. To reduce bias during gene expression integration across experiments we included only experiments performed on Affymetrix whole transcript array platform U133A, U133A 2.0, U133B, U133 plus 2.0 and U95A arrays.
Pre-processing of gene expression data
R and Bioconductor libraries were used for data pre-processing [51, 53]. The raw data for each gene expression dataset was retrieved. Pre-processing consisted of quality control using boxplots, arrayPLM and simpleaffy routines. For each experiment, samples were normalized using default parameters of the Robust Multi-Array algorithm  implemented in the affy library . To convert probe sets to gene expressions, we used the mean of the probe sets to represent the corresponding gene’s expression using the platform-dependent libraries in the Bioconductor project . Gene expressions for non-protein coding genes in the immunome protein dataset were removed.
The gene expression datasets were merged and batch effects were analyzed. We also performed PCA analysis before and after batch effect analysis to examine its effect and performance on the normalized datasets. The batch effects and PCA analysis were performed using the ComBat  and plotMDS algorithms implemented in the inSilicoMerging library  in Bioconductor.
Gene expression correlation
The mean of the jackknife Pearson correlation coefficient of the merged and pre-processed expression values for all gene pair combinations was calculated using the bootstrap library implemented in R. These correlation values were converted to absolute values and used as link weights for the immunome interactome.
Protein network filtering
We reconstructed the immunome PPI network as a weighted and undirected graph using the igraph package in R. The nodes, links, and link weights of the graph represent, respectively, the immunome protein coding genes, the PPIs and the average jackknife gene expression correlation between the immunome protein coding genes.
Network filtering was achieved with the GloSS algorithm , which identifies the relevant backbone of a weighted graph while retaining its weight distribution and structure. It uses a global null model to calculate the significance of the links by maintaining the topology of the network while assigning link weights randomly, from the observed weight distribution. The link weights (jackknife correlation coefficients) were multiplied by 100 to allow the p-values to be computed by GloSS. The computed link p-values by GloSS were used to filter the network by removing links in decreasing order of p-value. We monitored the filtering process to make sure that at least a path or connectivity remained between the TCR complex and NF-κB signaling pathways. The steps below represent the filtering procedure:
Step 1: Using GloSS, determine p-value for each edge of the network
Step 2: Select the link with the largest p-value
Step 3: Remove the link from the network
Step 4: Check for presence of connectivity between the NF-κB components and the TCR complex
Step 4.1: If connectivity exists discard the link and go to step 2.
Step 4.2: If connectivity does not exist, return the link to the network and stop.
represents the fraction of the filtered nodes. The igraph package was used to calculate the network scores .
Robustness of the T cell PPI network
Link weight-randomized networks were created by randomizing the weights of a fraction of links, keeping the topology unchanged. The following fractions of links were used to create each of the link weight-randomized networks: 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 and 0.9. Thirty iterations were performed on each link weight-randomized network. For each iteration, a fraction of links were randomly selected, their weights randomly reassigned, the filtering procedure performed and network topology statistics calculated. Node degree, average path length, betweenness centrality of both the nodes and the links, clustering coefficient of the network, and the intersection between the TPPIN network and the link weight-randomized networks, were calculated. After the iterations for each link weight-randomized network, the average of each of the network topology statistics was retained.
Gene Ontology term enrichment, over-representation and semantic similarity analysis
The interconnected proteins in the TPPIN were subjected to GO  term enrichment analysis. The GO terms for the proteins in the immunome interactome were used as the background. Fisher's exact test of the hypergeometric distribution was calculated and correction for multiple comparisons was performed using the Benjamini-Hochberg procedure . The enrichment analysis was performed with Webgestalt . Semantic similarity between the immunome interactome and the TPPIN was calculated using the clusterSim routine of the GOSemSim library  (version 1.18.0) available in R/Bioconductor.
Analysis of essential genes
We retrieved the human orthologs of the mouse lethality genes from the Mouse Genome Informatics database . A gene was included in the set of lethality genes with the following criteria: phenotype contains the word “lethality”, the type of lethality annotation contains neither “partial” nor “wean”. After removing non-immunome genes and those without the above-mentioned lethality annotations, we calculated the hypergeometric distribution and Fisher’s exact test for significance. Essential genes were retrieved using the biomaRt package in R  and visualization of the TPPIN with essential genes was done using Cytoscape 2.8.3.
Pathway gene mapping
The TPPIN genes were mapped to the KEGG pathways using the KEGG pathway mapper tool .
We thank Marko Pesu for valuable discussions.
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