T Helper Cell Activation and Differentiation

See T cell activation generally See also cluster of differentiation molecules

Helper Cell Activation

Naive T cells continually recirculate between the blood and lymph systems. If a naive cell does not encounter antigen in a lymph node, it exits through the efferent lymphatics, ultimately draining into the throacic duct and rejoining the blood. If a native T cell recognizes an antigen-MHC complex on an appropriate antigen-presenting cell or target cell, it will be activated, initiating a primary response. A signal is generated which leads to activation of the genes encoding interleukin 2 (IL-2) and the receptor for IL-2. The secreted IL-2 then binds to the newly expressed receptor and autostimutes the T cell proliferation.

Naive T cells require at least two signals for activation. Both are provided by an antigen presenting cell, which is usually a dendritic cell. Signal 1 is provided by MHC peptide complexes binding to T cell receptors, while signal 2 is mainly provided by B7 costimulatory proteins binding to CD28 on the T cell surface. Following interaction of a T cell receptor with an antigen MHC complex, CD3 is thought to transduce the activation signal leading to T cell proliferation and secretion of cytokines. A variety of other accessory molecules such as CD4 play accessory roles in antigen recognition and T activation. CD4 binds to a domain of the class II MHC molecule.

In summary, activation occurs in peripheral lymphoid organs when these cells recognize foreign antigen on the surface of an antigen-presenting cell, such as a dendritic cell, macrophage or B cell. The antigen is in the form of peptide fragments that are generated by the degradation of foreign protein antigens inside the antigen presenting cell. The recognition process depends on the presence in the antigen presenting cell of MHC proteins, which bind these fragments, carry them to the cell surface and present them there along with a co-stimulatory signal to the T cells.

T helper cells can also be activated by superantigens.

Helper Cell Differentiation

Differentiation of precursor naive T cells into mature cytokine producing cells is initiated by stimulation of naive T cells through the TCR and also influenced by a large number of genetic and environmental variables including the cytokine milieu. See Factors Affecting Th1/Th2 development. Sustained TCR stimulation in the presence of IL-4 yield differentiated Th2 cells which silence the IFNy gene while activating the IL-4, IL-5, and IL-13 genes. Conversely, stimulation of naive T cells in the presence of IL-12 yields differentiated Th1 cells, which show the opposite pattern of cytokine expression, silencing the IL-4, IL-5, and IL-13 genes but transcribing INFy at high levels upon secondary stimulation. IL-12 and IL-4 act by means of the transcription factors signal transducers and activators of transcription (STAT4 and STAT6.  See cytokines secreted during T cell development

During Th2 differentiation, activation of GATA-3 by the TCR is amplified by Stat 6, and GATA-3 works across the IL-4 locus to sustain gene expression initiation through TCR-delivered signals. Auto-amplification of GATA-3 is crucial to the polarizing nature of the process. During Th1 differentiation, activation of T-bet during TCR activation leads to downstream activation of IFNy initiated during TCR-delivered signals. Although Stat4 serves to amplify activation at the IFNy locus, T-bet is amplified by stat1 signals generated in response to IFNy. Again, auto-amplifcation of T-bet serves to drive the inherent polarizing nature of the differentiative process.

The IL-4, IL-5 and IL13 genes are linked closely in an evolutionarily conserved cytokine gene cluster, which occupies syntenic regions of mouse chromosome 11 and human chromosome 5. It is believed that the development proceeds in two successive developmental stages. The first is triggered by T cell receptor (TCR) engagement and induces permissive chromatin modifications at the IL-4-IL13 locus and transcription of IL-4 and Il13. The second (after 48 h) requires cytokine signaling and either stabilizes/enhances (Th2-priming) or reversed (Th1-priming) the changes initiated in stage 1.