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T-helper

Helper T-cells are special subpopulations of CD4(+) T-cells that provide help to other cells of the immune system in mounting immune responses by causing cell activation or the secretion of cytokines. These cells are neither phagocytic nor cytotoxic. They are collectively being referred to also as effector T-cells or T-effector cells (abbr. also Teff cells).

Several distinct types of T-helper cells, designated Th1, Th2, and Th3, have been identified. These cells have different functions in immunity (Mosmann and Coffman, 1989). The molecular mechanisms underlying the evolution of these two different T-helper cell types from common precursors are still not completely known. Thp cells (p for precursor) are believed to be the precursor cells of Th0 cells. Th0 cells are believed to be precursor cells that develop into either Th1 or Th2 cells. Th0 cells can shift toward Th1 or Th2 in response to cytokines (Gajewski et al, 1994). Th0 cells can produce all cytokines found to be secreted into the conditioned medium of either Th1 cells or Th2 cells at low levels. NKT-cells show a Th0 pattern of cytokine secretion in that they secrete Th1 and Th2 cytokines even without stimulation. Cytokines and a number of costimulatory proteins (B7, for example) are known to have roles in the regulation of differentiation of T-helper cells into the different subtypes and to influence ratios of Th1 and Th2 cells.

Th1 cells (Mosmann et al, 1986; Cherwinsky et al, 1987; Mosmann and Coffman, 1989) stimulate strong cellular immunity but only weak and transient antibody responses. In general, Th1 responses are stimulated by intracellular pathogens (viruses, some mycobacteria, some yeasts, and some parasitic protozoans). These cells produce a number of cytokines known as Th1 cytokines or Type 1 cytokines and including IL2, IFN-gamma, IL12 and TNF-beta.

Th2 cells (Mosmann et al, 1986; Cherwinsky et al, 1987; Mosmann and Coffman, 1989) evoke especially strong antibody responses but relatively weak cellular activity. Th2 responses are usually elicited by free-living bacteria and other parasites. Th2 cells produce cytokines that are known as Th2 cytokines or Type 2 cytokines and include IL4, IL5, IL6, IL10, and IL13.

Distinct subpopulations of T-helper cells similar to those first identified by Mosmann et al (1986) in mice are found also in humans. However, the human subpopulations are not identical and display a less restricted cytokine profile in that the synthesis of IL2, IL6, and IL10 is not stringently restricted to a single subset (Del-Prete et al, 1991). It should be noted also that T-cells expressing both Type 1 cytokines and Type 2 cytokines have been identified during differentiation (Firestein et al, 1989; Kamogawa et al, 1993) and among terminally differentiated cells (Paliard et al, 1988), demonstrating that expression of these distinct cytokines profiles is not mutually exclusive.

Th3 cells are CD4(+) regulatory T-cells associated with immune mechanisms involving oral tolerance towards antigens (Groux et al, 1997; Weiner et al, 2001). These cells are characterised, among other things, by the secretion of TGF-beta and/or IL10. They have suppressive properties for Th1 and Th2 cells. Tr1 cells (T-regulatory 1 cells; see: regulatory T-cells) are similar to Th3 cells, but they secrete large amounts of IL10 and were first characterized on the basis of their role in preventing autoimmune colitis (Levings and Roncarolo, 2000; Groux et al, 1997). A unique subpopulation of T-helper cells are Th17 cells, which are characterized by the expression of IL17.

Th1 cells, but not Th2 cells, secrete IL2, IFN-gamma, and TNF-beta, whereas Th2 cells, but not Th1 cells, express IL4, IL5, IL6, and IL10. Murine Th2 cells, but not Th1 cells, also express P600, the human counterpart of which has been identified as IL13. A novel cytokine inducing the synthesis of IFN-gamma in Th1 cells has been identified recently as IGIF (and renamed IL18 (see also: Interleukins).

The fact that some of these cytokines have been designated type 1 or type 2 factors does not imply that these cytokines cannot be produced also by other cells. Producer cells other than T-cells expressing CD4 include CD8(+) T-cells, monocytes, natural killer cells, B-cells, eosinophils, mast cells, basophils, and other cells. This is why many immunologists define immune responses by the types of cytokines controlling these responses rather than by the types of cells. Also, the actions of Th1 and Th2 cells in humans are not as clear-cut as they are in the mouse, where these cells are the primary sources of the cytokines.

Both types of T-helper cells can influence and regulate each other by the cytokines they secrete. For example, IFN-gamma, secreted by Th1 cells, can inhibit the proliferation of Th2 cells. IL10, secreted by Th2 cells, can suppress Th1 functions by inhibiting cytokine production (see also: CSIF, cytokine synthesis inhibitory factor). The Th2 cytokine IL4 inhibits the differentiation and/or expansion of Th1 cells. It thus appears that these functional subsets of helper cells are mutually antagonistic such that the decision of which subset predominates within an infection may determine also its outcome. Through the activities of the cytokines produced, Th1 and Th2 cells can keep each other in check and prevent inflammatory reactions in response to pathogens getting out of control. However, imbalances may also precipitate inappropriate reactions. It is thought that some autoimmune disorders may involve overactive Th1 cells while the exacerbation of other conditions such as allergies may involve overactive Th2 responses.

Th1 and Th2 lymphocytes also express a different repertoire of receptors for chemokines (Bonecchi et al, 1998). Human Th1 cells preferentially express the chemokine receptors CXCR3 and CCR5, whereas Th2 cells display mostly CCR4 and some CCR3. The agonists for CXCR3, mig, I-TAC, and IP-10, have been shown to act as antagonists for the chemokine receptor CCR3 (Loetscher et al, 2001). I-TAC, mig, and IP10 compete for the binding of eotaxin to cells expressing CCR3 and inhibit migration and calcium ion changes induced in such cells by stimulation with eotaxin, eotaxin-2, MCP-2, MCP-3, MCP-4, and RANTES. Chemokines that attract Th1 cells by acting through the CXCR3 receptor may enhance the polarization of T-cell recruitment and tissue homing by blocking concomitantly the migration of Th2 cells in response to CCR3 ligands.

The term follicular B helper T-cells (also: follicular helper T-cells; follicular B-helper memory T-cells abbr. TFH cells) has been suggested for a subpopulation of T-helper cells that specifically localize to follicles (Breitfeld et al, 2000; Schaerli et al, 2000). These cells regulate the step-wise development of antigen-specific B cell immunity in vivo (Fazilleau et al, 2009). In peripheral blood these cells coexpress CD45R0 and the T-cell homing chemokine receptor CCR7. In secondary lymphoid organs, CD4(+) cells expressing CXCR5 lose expression of CCR7, which allows them to localize to B-cell follicles and germinal centers where they express high levels of CD40 ligand and ICOS. CD4(+) CD45R0(+) tonsillar T-cells expressing CXCR5 efficiently support the production of IgA and IgG. Analysis of the memory response reveals that long-lasting memory cells are found within the CD4(+) CD45R0(+) population expressing CXCR5. Bryant et al (2007) have reported that IL21 produced by follicular B helper T-cells potently stimulates the differentiation of B-cells into antibody-forming cells through the IL21 receptor. The generation of follicular B helper T-cells is closely associated with initiation of adaptive immunity and these cells thus play a central role in normal and pathological immune responses (Vinuesa et al, 2005; Moser and Ebert, 2003; Schaerli et al, 2001; King et al, 2008).

For other relevant entries see also: Cell types.

LAST MODIFIED: May 2009

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